Copy-editor: R. Camp
Last revision: 23 May 2021
This chapter is partly not up-to-date!
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As of 23 May 2021, four COVID-19 vaccines have been approved or authorized for emergency use in the EU or the US (see also Table 1):
- The BioNTech/Pfizer vaccine. Trade name: Comirnaty™ (tozinameran, formerly known as BNT162b2)
- The Moderna vaccine, also known as mRNA-1273
- The AstraZeneca/University of Oxford vaccine. Trade name: Vaxzevria™/Covishield™ (formerly known as ChAdOx1 nCoV-19, AZD1222)
- The Johnson & Johnson (Janssen) vaccine, also known as Ad26.COV2.S
Outside the EU and the US, four other vaccines have been approved:
- BBIBP-CorV, Sinopharm and the Beijing Institute of Biological Products – first approved in China on 30 December 2020
- Covaxin, Bharat Biotech – first approved in India on 3 January 2021
- Sputnik-V, Gamaleya Research Institute – first approved in Russia, 28 December 2020
- Convidecia, CanSinoBIO – first approved in China, 25 February 2021
|Table 1. SARS-CoV-2 vaccines approved in Europe (EMA) and the US (FDA)|
(Tozinameran, formerly BNT162b2)
–25°C to -15°C for a max. of two weeks
|16+ years||2 x 3 weeks apart||Polack 2020
Mulligan 2020FDA EUA
FDA briefing doc
Sponsor briefing docRecommendation for use
|18+ years||2 x 4 weeks apart||Polack 2020
Jackson 2020FDA EUA
FDA briefing doc
Sponsor briefing docRecommendation for use
Oxford UniversityVaxzevria™ (formerly AZD1222, ChAdOx1 nCoV-19)
Suspended (see below*)
|2 x up to 12 weeks apart||Voysey 2020
Folegatti 2020MHRA Decision
|Johnson & Johnson
|18 years and older||1 x||FDA 20210226
After an unusually frequent occurrence of cerebral sinus vein thromboses less than two weeks after injection of the AstraZeneca vaccine (mostly in younger women), several European countries stopped the use of the vaccine (Netherlands, Denmark, Norway) or restricted its use to people > 55 years of age (France, Canada), > 60 (Germany) or > 65 (Sweden, Finland). German authorities are now considering offering a second injection with another vaccine.
In December 2020, a Belgian minister tweeted the price that the EU had agreed to pay for COVID vaccines (The Guardian). The University of Oxford/AstraZeneca vaccine is the cheapest and Moderna is the most expensive:
- BioNTech/Pfizer: €12
- Moderna/NIAID: $18
- University of Oxford/AstraZeneca: €1.78 (£1.61)
- Johnson & Johnson: $8.50 (£6.30)
Initially, AstraZeneca had pledged it would provide doses on a cost basis for at least as long as the pandemic lasts and in poorer countries in perpetuity. However, according to a newspaper article, an agreement between AstraZeneca and a Brazilian manufacturer seem to define the “Pandemic Period” as ending on July 1, 2021. The period could be extended but only if “AstraZeneca acting in good faith considers that the SARS-COV-2 pandemic is not over” (Financial Times, 8 October 2020).
The currently licensed COVID-19 vaccines offer very good protection against infection with the Wuhan strain and the B.1.1.7 variant. The estimated effectiveness of the BioNTech/Pfizer vaccine after the second dose was 92% for documented infection, 94% for symptomatic COVID-19, 87% for hospitalization, and 92% for severe COVID-19 (Dagan 2021). A protective effect of up to 80% has been shown as soon as two weeks after the first injection (Dagan 2021, Pilishvili 2021) (Table 2).
|Table 2. Effectiveness of the BioNTech/Pfizer vaccine in Israel (2 x 596,618 persons) (Dagan 2021). Find more sub-population data at https://bit.ly/3eMlSfS.|
|14 through 20 days after the first dose||21 through 28 days after the first dose||7 days after the second dose and later|
The results of this Phase IV analysis from Israel are important in two ways. First, they describe a COVID-19 vaccine under real-life conditions, matching almost 600,000 vaccinees to an equal number of unvaccinated controls according to demographic and clinical characteristics. This figure is almost 30 times the number of participants in the Phase III study by Polack et al. (n = 21,720; Polack 2020). Second, the trial took place in an epidemiological environment where the B.1.1.7 variant was the dominant lineage. This is comforting news for countries where B.1.1.7 has become or is becoming the dominant strain.
Other Phase IV analyses confirm the efficacy of the COVID-19 vaccines:
- Two weeks after administration of the first COVID-19 vaccine dose, the risk of SARS-CoV-2 infection, hospitalization and death progressively decreases up to about 35 days, both in men and women and in people of different age groups. These are the results of a study by the Italian National Institute of Health (Istituto Superiore di Sanità, ISS) which analyzed 7,370,008 individuals vaccinated as of 4 April 2021. 65% of the study population had received the first injection of the BioNTech/Pfizer vaccine, 6% the first Moderna and 29% the first AstraZeneca injection (Pezzotti 2021) . The authors describe a
- ~80% reduction for the risk of receiving a diagnosis of SARS-CoV-2 infection
- 90% reduction for the risk of hospitalization
- 95% reduction for the risk of death (see Figure 1)
Figure 1. Reduction of the risk of diagnosis and subsequent death at different time intervals from administration of any first dose of the BioNTech/Pfizer, Moderna or AstraZeneca vaccine, starting from the beginning of the vaccination cycle compared to the period 0-14 days from the first dose (reference period).
- Vasileiou 2021, Hall 2021, Public Health England 20210222: The vaccines used in Scotland and England – BioNTech/Pfizer and AstraZeneca – protected well over 80% of vaccinees against COVID-19-related hospitalization at 28-34 days post-vaccination, even aged ≥ 80 years, and even after a single dose.
- Thompson 2021: In a prospective cohort of 3950 health care personnel, first responders, and other essential and frontline workers who completed weekly SARS-CoV-2 testing for 13 consecutive weeks, mRNA (BioNTech/Pfizer or Moderna) vaccine effectiveness of full immunization (≥ 14 days after second dose) was 90% against SARS-CoV-2 infections regardless of symptom status; vaccine effectiveness of partial immunization (≥ 14 days after first dose but before second dose) was 80%.
- In a prospective, UK population-representative cohort study of 373,402 participants aged ≥ 16 years, the odds of new SARS-CoV-2 infection were reduced 65% in the ≥ 21 days since first vaccination with the BioNTech/Pfizer or Oxford-AstraZeneca vaccine (Pritchard 2021). Older and more vulnerable people were as protected as younger healthy individuals. A second dose of the BioNTech/Pfizer vaccine boosted protection further, reducing symptomatic infections by 90% and asymptomatic infections by 70%. Vaccination also reduced SARS-CoV-2 infections with evidence of high viral shedding Ct < 30 (88% reduction after two doses) and with self-reported symptoms (90% reduction after two doses).
The onset of protection for the BioNTech/Pfizer and the Moderna vaccines (both mRNA vaccines) was observed as early as 12 days after the first dose. An analysis of the serological and T cell response after the first dose of the BioNTech/Pfizer vaccine showed that 80% of vaccinees developed spike-binding antibodies at day 10 after the first dose and 100% developed spike-specific T cells at the same time point. The authors suggest that early T cell and binding antibody responses, rather than either receptor blocking or virus neutralizing activity, might be correlates of early protection against COVID-19 (Kalimuddin 2021).
B.1.351-like variants currently include B.1.351 (first detected in South Africa) and P.1 (Brazil). Both strains harbor the E484K mutation (Tegally 2021, Voloch 2020) which is the “bad boy on the block”. Results from clinical vaccine trials (Table 3) have shown that the level of protection against moderate to severe COVID-19 infection was lower in South Africa where B.1.351 has been the predominant variant of late:
- The Johnson & Johnson vaccine provided a level of protection against moderate to severe COVID-19 infection of 57% in South Africa and 72% in the United States (JNJ 20210129).
- The not yet approved Novavax vaccine candidate provided a level of protection against mild and moderate-to-severe COVID-19 infection of only 49% in South Africa (Novavax 20210311).
- The AstraZeneca vaccine performed poorly in South Africa – no protection against mild-moderate COVID-19 due to B.1.351 (Madhi 2021).
|Table 3. Vaccine efficacy against new variants|
|Vaccine manufacturer||Participants||Main efficacy findings|
|Efficacy against B.1.1.7|
|Novavax||15,203||86% efficacy (vs 96% for historical variant)|
|AstraZeneca||4236||75% efficacy (vs 85% for historical variant)|
|Efficacy against B.1.351|
|Johnson & Johnson
|~10,900||57% efficacy (72% in US)|
– HIV negative: 55%
– HIV positive: probably substantially lower
|AstraZeneca||~2000||“minimal protection vs mild-moderate infection”|
These results were anticipated by in vitro studies which showed that B.1.351-like variants have a higher potential for evasion of natural or vaccine-induced immunity than B.1.1.7. A map of all amino acid mutations to the SARS-CoV-2 spike receptor-binding domain (RBD) showed that the site where mutations tended to have the largest effect on antibody-binding and neutralization was E484 (Greaney 2021b). Another study by David H. Ho and colleagues found that the serum of 12 people vaccinated with Moderna’s vaccine and 10 people vaccinated with the BioNTech/Pfizer vaccine was 10 to 12 times less potent against B.1.351 (Wang P 2021). In serum from 20 people previously infected with SARS-CoV-2 the drop in plasma neutralization against B.1.351 was 9-fold. E484K accounted for much of the effect.
P.1, the variant first detected in Brazil, was also more resistant to neutralization by (first-wave) convalescent plasma (de Souza 2021, Wang P 2021, Faria 2021). Plasma from individuals vaccinated with the Chinese CoronaVac vaccine, too, failed to efficiently neutralize P.1 lineage isolates (de Souza 2021).
A recent paper reports that the BioNTech/Pfizer vaccine did not prevent an outbreak of the B.1.351 variant (first detected in South Africa) in a French nursing home; however, it reduced transmission: all unvaccinated residents (5/5), but only half of the vaccinated residents (13/26) were infected (Bailly 2021). The SARS-CoV-2 viral load was significantly higher in non-vaccinated residents (mean cycle threshold (Ct) value: 15, range 12-17) than in vaccinated residents (mean Ct: 21, range: 13-32). The vaccine also reduced disease severity. Among the vaccinated residents who were infected, 2 (15.4%) were asymptomatic and 9 (69.2%) had mild to moderate disease; two individuals (15.4%) had severe disease and died. Among the 5 non-vaccinated residents, 4 progressed to severe disease; one of them died.
The current – preliminary – state-of-knowledge can be summarized as follows:
- While natural and vaccine-induced immunity is likely to protect against infection with B.1.1.7, it may be insufficient to fully protect against B.1.351, P.1, and P.1.617.2.
- However, even in the absence of antibody neutralization, we should expect some T cell protection (Tarke 2021)
- Several vaccines may provide satisfying immunity against SARS-CoV-2 variants
- Most vaccines will probably provide protection against hospitalizations/deaths from these variants
- A booster vaccine against these variants is likely to be effective
mRNA vaccines have recently been shown to be exquisitely effective also in adults aged ≥ 65 years (Tenforde 2021) with a:
- 94% protection among individuals who were fully vaccinated
- 64% among individuals who were partially vaccinated (defined as onset of COVID-like illness 14 days or later after the first dose but less than 14 days after the second dose)
- No protection during the first 14 days after the first vaccine dose
Half of the patients in this study were 75 years or older.
An analysis of more than 35,000 pregnant women 16 to 54 years of age showed that injection-site pain was reported more frequently among pregnant women, whereas headache, myalgia, chills, and fever were reported less frequently (Shimabukuro 2021b). Among almost 4000 women enrolled in the v-safe pregnancy registry, 827 had a completed pregnancy. The frequency of miscarriage (Quenby 2021), preterm birth, small size for gestational age, congenital anomalies, and neonatal death didn’t appear to be different from data published before the COVID-19 pandemic.
In a small cohort study, 30 pregnant and 16 lactating women developed both humoral and cellular immune responses after vaccination with the BioNTech/Pfizer or the Moderna vaccine. Vaccine-elicited antibodies were also found in infant cord blood and breast milk (Collier 2021).
Breakthrough infections even among fully vaccinated persons (Hacisuleyman 2021) will be daily bread and butter over the coming months. The clinical course is expected to be generally milder than in unvaccinated individuals. In one recent study, two thirds of breakthrough infections among persons in skilled nursing facilities (SNF) were asymptomatic (Teran 2021) and no facility-associated secondary transmission was identified. Another study estimated that unvaccinated SNF residents and health care personnel (HCP) had 3.0 and 4.1 times the risk of infection compared to vaccinated residents and HCP. Vaccine was 86.5% protective against symptomatic illness among residents and 87.1% protective among HCP (Cavanaugh 2021).
Although local or systemic side effects are frequent – mostly pain at injection site, fatigue, headache, muscle pain, joint pain, and sometimes fever during the first 24 to 48 hours after vaccination (Folegatti 2020, Voysey 2020, Jackson 2020, Mulligan 2020, Polack 2020, Baden 2020) – more severe side effects have been in the single-digit range. As a general rule, side effects appear to be more common after the second dose, and younger adults experience more side effects than older adults. The frequency of reported reactions has since been confirmed by real-world observations of more than 3 million people (Chapin-Bardales 2021) through v-safe, a surveillance system for collecting near–real-time data from COVID-19 vaccine recipients in the US.
In the Phase III studies of the BioNTech/Pfizer and Moderna vaccines, serious side effects were equally rare in people who received the vaccine and those who received placebo (Polack 2020, Baden 2020). Anaphylactic reactions may occur in 1 of 100,000 vaccine recipients (see page 22). In the initial trials, no other safety warnings had been found, and the risk of serious adverse effects remains remarkably low after administration of a billion vaccine doses by the end of April 2021. In mid-February, just 20 cases of patients with thrombocytopenia and bleeding without thrombosis after vaccination with the mRNA–based vaccines produced by BioNTech/Pfizer and Moderna had been reported (Lee EJ 2021).
Then, still in February, suddenly, the first and until now only truly worrisome adverse event of COVID-19 vaccines was reported: life-threatening thromboses, together with thrombocytopenia and sometimes bleeding that occurred as early as 4 days after injection of the AstraZeneca vaccine.
As of 26 April, several hundred cases of unusual thrombosis in veins in the brain (cerebral sinus vein thromboses, CSVT), the abdomen (splanchnic vein thrombosis) and in arteries were reported after the first injection of the AstraZeneca vaccine. The first symptoms appeared as early as five days and as late as a month after vaccination. Cases of the new syndrome – vaccine-induced immune thrombotic thrombocytopenia (VITT) or thrombosis-thrombocytopenia syndrome (TTS) – have been reported from several countries, including Germany and Austria (Greinacher 2021), Norway (Schultz 2021), France (ANSM 20210416), and the UK (MHRA 20210401, Scully 2021). By April 21, the Paul-Ehrlich-Institut (PEI), Germany’s vaccine regulator, had registered 59 cases (14 men and 45 women) of this syndrome. Of the 43 women for whom the time interval between vaccination and the onset of symptoms is known, 38 were between 22 and 59 years old. Twelve of the 14 men affected were 20 to 59 years old, the other two were between 60 and 70. The symptoms began in 57 of the 59 cases within 29 days of the vaccination. Twelve people died, six men and six women. With around 4.2 million vaccinated with the AstraZeneca vaccine, the risk for vaccine-induced immune thrombotic thrombocytopenia (VITT) was around one case in 70,000 vaccinated; for women, the risk was higher. In Norway, five health care workers 32 to 54 years of age had venous thrombosis and thrombocytopenia 7 to 10 days after receiving the first dose of the AstraZeneca vaccine. Three patients died. The five cases occurred in a population of around 130,000 vaccinated persons (1:26,000) (Schultz 2021; see also Pottegård 2021, Hunter 2021).
Up to 14 April 2021, UK authorities were aware of 168 cases of major thromboembolic events with concurrent thrombocytopenia following vaccination with the AstraZeneca vaccine. These events occurred in 93 women (55%) and 75 men aged from 18 to 93 years. A total of 32 deaths occurred (fatality rate: 19%) (MHRA 20210422). Cerebral venous sinus thrombosis was reported in 77 cases (average age 47 years) and 91 had other major thromboembolic events (average age 55 years) with concurrent thrombocytopenia. With 21.2 million administered by 14 April, the risk was 1 in 126,000 administrations. The data also suggest that there was a higher incidence in younger adult age groups. The MHRA advised that this “evolving evidence should be taken into account when considering the use of the vaccine”.
Young age and female gender were initially thought to be at increased risk for VITT; in the study from Germany and Austria, 9 of the 11 patients were women and most were relatively young adults (median age: 36; range, 22 to 49). However, higher age and male gender should not induce physicians to exclude VITT. French reports describe a total of 34 cases of atypical thrombosis cases out of more than four million injections, including 11 deaths (ANSM 20210517, 17 May). The mean age of recent cases was in the 60s and half of them were men (ANSM 20210416, 16 April; ANSM 20210423, 23 April).
A tentative mechanism by which the AstraZeneca vaccine might trigger an immune response leading to VITT (–> highly reactive anti-PF4 antibodies with downstream FcγIIa receptor-dependent amplification; –> recruitment of neutrophils; –> neutrophil activation and NETs formation; –> triggering a prothrombotic response) has recently been proposed in a pre-print (Greinacher 2021b).
The clinical picture of thrombocytopenia and thrombotic complications at unusual sites one to four weeks after the administration of the AstraZeneca vaccine reflects an immunologic pattern similar to that of severe heparin-induced thrombocytopenia (HIT), a prothrombotic disorder caused by platelet-activating antibodies that recognize multi-molecular complexes between cationic PF4 and anionic heparin (Greinacher 2015). The clinical presentation of vaccine-induced immune thrombotic thrombocytopenia (VITT) may be entirely unspecific (headache, backache, chills, fever, nausea, epigastric discomfort) or highly suggestive (stroke or reduced consciousness after three days of headache; Schultz 2021), especially when physicians are informed about administration of the AstraZeneca vaccine in the previous 4 weeks. A paper from Germany and Austria describes thrombotic events including cerebral venous thrombosis (in 9 patients), splanchnic vein thrombosis (in 3 patients), pulmonary embolism (in 3 patients), and other types of thrombi (in 4 patients); 5 of 10 patients had more than one thrombotic event (Greinacher 2021). All patients presented with concomitant thrombocytopenia (median nadir of platelet count, approximately 20,000 per cubic millimeter; range, 9000 to 107,000). A paper from Norway describes five cases that occurred 7 to 10 days after the first injection of the AstraZeneca vaccine. Four of the patients had severe cerebral venous thrombosis with intracranial hemorrhage (Schultz 2021). Three patients died.
In the context of mass vaccination with the AstraZeneca vaccine, clinicians should be aware that rarely, venous or arterial thrombosis can develop at unusual sites within the first months after vaccination. Clinicians should have a low threshold for requesting ELISA testing for PF4–polyanion antibodies, including confirmatory functional testing, in patients who have
- Single or multiple thromboses in unusual locations:
- Cerebral venous sinus thrombosis (CVST)
- Thrombosis of portal, splanchnic, or hepatic veins
- Pulmonary emboli
- Acute arterial thromboses
- Low platelet counts. In the Greinacher study, the mean was 35,000 per mm3 (range, 8000 to 107,000; Greinacher 2021)
- High levels of d-dimers
- Low levels of fibrinogen
To detect PF4-specific antibodies in patients with suspected VITT, the use of a sensitive, quantitative, immunologic test is strongly recommended. Rapid immunoassays should be avoided (Vayne 2021).
Positive PF4/polyanion enzyme immunoassays (EIAs) can occur after SARS-CoV-2 vaccination with both mRNA- and adenoviral vector-based vaccines. In a recent study, the EIA was found to be positive in 19 of 281 vaccinees (all: 6.8%; BioNTech/Pfizer: 5.6%; AstraZeneca: 8.0%); however, optical densities were mostly between 0.5-1.0 units (reference range, < 0.50) and none of the PF4/polyanion EIA-positive samples induced platelet activation in the presence of PF4 (Thiele 2021). In most cases, these antibodies are likely to have only minor (if any) clinical relevance.
Find a diagnostic algorithm and therapeutic strategies for the management of suspected VITT at Greinacher 2021.
As for now, no predisposing factors for VITT have been identified. There is no indication that a history of thrombosis, HIT or other risk factors (i.e., birth control pills) increase the risk of VITT.
VITT is treatable if identified quickly. On 29 March, the German GTH (Gesellschaft für Thrombose- und Hämostaseforschung – Society for Thrombosis and Hemostasis Research) suggested that the prothrombotic pathomechanism could likely be interrupted by the administration of high-dose intravenous immunoglobulins (IVIG), i.e., at a dose of 1 g per kg of body weight daily on two consecutive days (Oldenburg 2021). Intravenous immunoglobulin and high-dose glucocorticoids can improve the platelet count within days.
It is yet unclear whether delaying anticoagulation until after initial disease control with IVIG or plasma exchange is beneficial (Scully 2021). Reluctance to start anti-coagulation with non-heparin anti-coagulant agents such as argatroban, danaparoid, or fondaparinux may be tempered by administering high dose of IVIG to raise the platelet count, especially when a patient presents with severe thrombocytopenia and thrombosis, such as cerebral venous thrombosis (Greinacher 2021).
Treatment with platelet transfusions should be avoided because they would provide a substrate for further antibody-mediated platelet activation and coagulopathy (Scully 2021).
With earlier recognition and aggressive treatment, the high mortality rate of VITT is likely to decrease.
Over the coming weeks and months, we might see more unusual clinical pictures in previously healthy individuals after the administration of the AstraZeneca or the Johnson & Johnson vaccine, such as, for example, superior ophthalmic vein thrombosis (SOVT) + immune thrombocytopenia + ischaemic stroke (Bayas 2021). In many cases, it will be delicate to establish or refute a causal relationship with the vaccination.
The following questions, recently summarized by Douglas Cines and James Bussel (Cines & Bussel 2021), will need to be addressed soon:
- What component or components of the vaccine (adenoviral sequence, spike protein, or other component) elicit this new (or recall) response to a seemingly unrelated host protein, PF4?
- What is the risk after re-vaccination?
- How do VITT antibodies compare with the anti-PF4–related antibodies that are present after SARS-CoV-2 infection, which have been described in patients who were suspected to have heparin-induced thrombocytopenia?
- Is PF4 a bystander component within an immune complex that activates platelets, or does it contribute directly to clot propagation?
- Does the atypical distribution of thrombi relate to antigen localization or vascular response?
- Is thrombosis propagated along vascular and hematopoietic surfaces that release diverse anionic co-factors, as in heparin-induced thrombocytopenia?
And yet another question:
- Do mild – undiagnosed – forms of VITT exist? If yes, could these predispose people to clinically relevant thrombotic events in the future?
VITT has devastating effects for otherwise healthy young adults and requires a thorough risk–benefit analysis (Schultz 2021). In late March, several European countries stopped using the AstraZeneca vaccine (Denmark, Norway) or restricted its use to people > 55 years of age (France, Canada), > 60 (Germany) or > 65 (Sweden, Finland). In Spain, where rules change frequently, it is restricted to those between 60 and 69.
On 7 April, EMA announced that unusual thrombosis and thrombocytopenia should be listed as very rare side effects of the AstraZeneca vaccine (EMA 20210407). Healthcare professionals should tell people receiving the vaccine that they must seek medical attention if they develop:
- symptoms of blood clots such as shortness of breath, chest pain, leg swelling, persistent abdominal pain
- neurological symptoms such as severe and persistent headaches and blurred vision
- petechiae beyond the site of vaccination after a few days.
Although the EMA stated that the overall benefits of the AstraZeneca vaccine in preventing COVID-19 outweighed the risks of side effects, the agency also specified that the “use of the vaccine during vaccination campaigns at national level will also take into account the pandemic situation and vaccine availability in the individual Member State (EMA 20210407).” The British Joint Committee on Vaccination and Immunisation (JCVI) issued a less ornate and more cautious recommendation, advising that it is preferable for adults aged less than 40 years to be offered an alternative COVID-19 vaccine, if available (JCVI 20210507) (unless they have underlying health conditions and only if this does not cause substantial delays in being vaccinated). Some physicians, especially those in private practice, might feel more comfortable administering alternative vaccines even in those older than 40 years.
EMA’s human medicines committee analyzed the vaccine’s benefits and the risk of unusual blood clots with low platelets in different age groups in the context of the monthly infection rates: low (55 per 100,000 people = 18 daily infections per 1,000,000 people), medium (401 per 100,000 people = 133 daily infections per 1,000,000 people) and high (886 per 100,000 people = 295 daily infections per 1,000,000 people) (EMA 20210423). The following three tables show the potential benefits and harms of the AstraZeneca for a low (Table 4a), medium (Table 4b) and high (Table 4c) transmission rate scenario.
|Table 4a. Weighing up the potential benefits and harms of the AstraZeneca vaccine in a low transmission rate scenario*. Expected VITT cases and number of prevented 1) hospitalizations, 2) ICU admissions and 3) deaths after vaccination with the AstraZeneca vaccine.|
(considering an 80% vaccine effectiveness over a period of four months)
|Age group||Thromboses (VITT**; also called TTP)||Hospitalizations||ICU admission||Deaths|
* Low infection rate defined a monthly incidence of 55/100,000 population which corresponds to a daily incidence of 18/1,000,000. Examples: US: 23 March 2020; France: 4 August 2020; Germany: 17 September 2020; Italy: 27 August 2020; Spain: 16 July 2020. From: AstraZeneca’s COVID-19 vaccine: benefits and risks in context. Medicines Agency (EMA) 2021, published 23 April (EMA 20210423)
** VITT: Vaccine-induced thrombosis with thrombocytopenia
= TTP: Thrombosis with thrombocytopenia
|Table 4b. Weighing up the potential benefits and harms of the AstraZeneca vaccine in a medium transmission rate scenario*. Expected VITT cases and number of prevented 1) hospitalizations, 2) ICU admissions and 3) deaths after vaccination with the AstraZeneca vaccine.|
(considering an 80% vaccine effectiveness over a period of four months)
|Age group||Thromboses (VITT**; also called TTP)||Hospitalizations||ICU admission||Deaths|
* Medium infection rate defined a monthly incidence of 401/100,000 population which corresponds to a daily incidence of 133/1,000,000. Examples: US: 22 Septemer 2020; France: 18 September 2020; Germany: 27 October 2020; Italy: 18 October 2020; Spain: 27 March 2021. From: AstraZeneca’s COVID-19 vaccine: benefits and risks in context. Medicines Agency (EMA) 2021, published 23 April (EMA 20210423)
** VITT: Vaccine-induced thrombosis with thrombocytopenia
= TTP: Thrombosis with thrombocytopenia
|Table 4c. Weighing up the potential benefits and harms of the AstraZeneca vaccine in a high transmission rate scenario*. Expected VITT cases and number of prevented 1) hospitalizations, 2) ICU admissions and 3) deaths after vaccination with the AstraZeneca vaccine.|
(considering an 80% vaccine effectiveness over a period of four months)
|Age group||Thromboses (VITT**; also called TTP)||Hospitalizations||ICU admission||Deaths|
* High infection rate defined a monthly incidence of 886/100,000 population which corresponds to a daily incidence of 295/1,000,000. Examples: US: 3 November 2020; France: February 2020; Germany: Christmas 2020; Italy: 2 March 2021; Spain: 21 October 2020. From: AstraZeneca’s COVID-19 vaccine: benefits and risks in context. Medicines Agency (EMA) 2021, published 23 April (EMA 20210423)
** VITT: Vaccine-induced thrombosis with thrombocytopenia
= TTP: Thrombosis with thrombocytopenia
These figures show how the risks outweigh the benefits of the vaccine 1) the lower the infection rates and 2) the younger the recipients. In other words:
- For younger people, the risk-benefit balance is worse than for older people
- For people living in an environment with low infection rates the risk-benefit balance is worse than for people in an environment with high-infections rates
It is evident that as more young people become eligible to be vaccinated, alternative vaccines (i.e., BioNTech/Pfizer, Moderna) will become more attractive.
Cases of cerebral venous sinus thrombosis (CVST) concomitant with thrombocytopenia have also been described after vaccination with the Johnson & Johnson vaccine (Muir 2021, Sadoff 2021). After a short pause (FDA 20210413), the FDA and the CDC recommended on 23 April to resume the use of the Johnson & Johnson vaccine (FDA 20210423). At that time, the agencies were aware of 15 cases reported to the Vaccine Adverse Event Reporting System VAERS. All cases occurred in women between the ages of 18 and 59, with a median age of 37 years. Symptom onset was between 6 and 15 days after vaccination.
After a “plausible” link (EMA 20210407) between the AstraZeneca vaccine and rare life-threatening thromboses together with thrombocytopenia, it is unclear if the vaccine will be approved by the FDA. If it is approved, it is unclear if it will be used in the US – the country has a huge supply of alternative vaccines. On 26 April, a senior US administration official was quoted saying that there could be “up to 60 million doses of the AstraZeneca vaccine available to be shared with other countries in the next two months” (Collins 2021).
A relatively low number of cerebral sinus vein thromboses and splanchnic vein thromboses have reshaped the landscape of COVID vaccines. In the European Union, some countries have stopped using the AstraZeneca vaccine (Denmark) or will lend all of its more than 200,000 doses of AstraZeneca to neighbouring Iceland and Sweden (Norway). Other countries restrict the use of the vaccine to people over 55, 60 or 65. The European Union has not canceled its existing orders of the AstraZeneca and Johnson & Johnson vaccines, but signaled it might not be going to be placing more (NYTimes 20210414). As COVID vaccine scarcity will soon tip over into vaccine abundance in a growing number of countries, the future market for the AstraZeneca vaccine will need to be defined.
On December 8, 2020, within 24 hours of the start of the UK vaccination program, probable cases of anaphylaxis were reported in two women in their forties, who had known food and drug allergies and were carrying auto-injectable epinephrine (Castells 2020). One week later, a 32-year-old female health care worker in Alaska who had no known allergies presented with an anaphylactic reaction within 10 minutes of receiving the first dose of the vaccine. Since then, several more cases of anaphylaxis associated with the Pfizer mRNA vaccine have been reported after vaccination of almost 2 million health care workers, and the incidence of anaphylaxis associated with the Pfizer SARS-CoV-2 mRNA vaccine appears to be approximately 10 times as high as the incidence reported with all previous vaccines, at approximately 1 in 100,000, as compared to 1 in 1,000,000 (Castells 2020, Shimabukuro 2021).
An analysis of the constituents of mRNA vaccines shows that an anaphylactic reaction may be due to several factors which cannot be determined in clinical practice (see Risma 2021). A recent study of three individuals with a history of PEG allergy and three healthy controls found that the BioNTech/Pfizer vaccine induced positive skin tests in PEG allergic patients, whereas traditional PEG skin testing was negative in two of three patients. As an effect could be induced by PEGylated liposomal doxorubicin, the authors suggest that PEGlyated lipids within nanoparticles, and not PEG in its native state, could be a potential trigger of anaphylaxis to the BioNTech/Pfizer vaccine (Troelnikov 2021).
However, it may still be possible to safely vaccinate people with allergies to vaccine components after assessing patients who report allergy to a vaccine, injectable medication, or PEG. Consult an allergist who might triage patients into those able to go ahead with vaccination with the routine 15 minutes of observation, those requiring 30 minutes of observation, and those who require skin testing to PEG and polysorbate before vaccination (Glover 2021, Mustafa 2021).
The CDC recommends that appropriate medical treatment for severe allergic reactions be immediately available in the event that an acute anaphylactic reaction occurs following administration of an mRNA COVID-19 vaccine (CDC 20201231, CDC 20210303). In particular, persons without contraindications to vaccination who receive an mRNA COVID-19 vaccine should be observed after vaccination for the following time periods:
- 30 minutes: Persons with a history of an immediate allergic reaction of any severity to a vaccine or injectable therapy and persons with a history of anaphylaxis due to any cause.
- 15 minutes: Everyone else
Could post-exposure vaccination with SARS-CoV-2 vaccines be able to mitigate COVID-19 disease? Claude Muller of the Luxembourg Institute of Health argues that there might be enough time for protective vaccine effects to set in (Muller 2021):
- The time from SARS-CoV-2 infection to hospitalization is around two weeks:
- Incubation time of SARS-CoV-2 infection: 5 days (Elias 2021)
- Time from symptom onset to hospitalization: around 7 to 10 days
- Partial protection from mRNA vaccines has been shown as early as two weeks after the first vaccine dose (Polack 2020, Dagan 2021)
In particular, individuals with a long incubation period could benefit from post-exposure vaccination. While a large randomized control trial would be needed to demonstrate the efficacy of this approach, post-exposure SARS-CoV-2 vaccination would cause no harm and could only benefit the vaccine recipients (Muller 2021). Post-exposure vaccination is not new – protection is quite high in a number of infectious diseases (hepatitis A, 85%; hepatitis B, 85%; measles, 83%; varicella, 67%; smallpox, 45%; and mumps, 38%) (Gallagher 2019).
Current evidence indicates that only one vaccine dose is needed to maximize immune protection in individuals who survived a previous SARS-CoV-2 infection (Manisty 2021, Krammer 2021, Reynolds 2021). In these cases, the pre-vaccination SARS-CoV-2 infection is analogous to immune priming and the first vaccine dose analogous to the (second) booster injection. It would even seem that protection provided by a previous SARS-CoV-2 infection plus a single BioNTech/Pfizer vaccine dose is superior to ‘No previous COVID-19’ plus two vaccine doses. A high degree of protection provided by 1) a pre-vaccination SARS-CoV-2 infection plus 2) one vaccine dose has been suggested/shown by:
- Antibody titers measured in participants of clinical mRNA vaccine trials (Krammer 2021, Saadat 2021). In the Krammer study, no increase in antibody titers was observed in people with pre-vaccination SARS-CoV-2 infection who received the second vaccine dose.
- T and B cell responses after a single dose of the BioNTech/Pfizer vaccine (Reynolds 2021). A single dose showed:
- Enhanced T cell immunity
- Antibody secreting memory B cell response to spike
- Effective neutralizing antibodies against the B.1.1.7 and B.1.351 variants (by comparison, a single vaccine dose without prior infection showed only reduced immunity against variants)
- A significant increase of all components of the humoral response with serum neutralizing activities against variants of concern comparable to or greater than neutralizing activity achieved by vaccination of naïve individuals against the historical strain (Wang Z 2021)
- A study that measured antibody and memory B cell responses in 33 SARS-CoV-2 naïve and 11 SARS-CoV-2 recovered subjects (Goel 2021)
- A study of 500 employees of a 350-bed hospital in Israel (Abu Jabal 2021)
- A study of 102 residents from nursing homes in Montpellier, France (Blain 2021)
- A study of 124 Italian healthcare professionals (Levi 2021)
- A study of SARS-CoV-2 spike-specific T and B cell responses, as well as specific IgA, IgG, IgM and neutralizing antibody titers in 22 individuals in Florence, Italy, 11 of which had a previous history of SARS-CoV-2 infection (Mazzoni 2021)
- A study of 51 health-care workers in London (Manisty 2021)
A recent preprint reports that T cells from individuals with pre-vaccination SARS-CoV-2 infection differed from those of infection-naive vaccinees (five of the participants had received the BioNTech/Pfizer vaccine and three the Moderna one) (Neidleman 2021). Compared to SARS-CoV-2-naive individuals, previously infected people might even have a superior long-term persistence of nasopharynx-homing SARS-CoV-2-specific T cells.
Table 5 presents 6 situations: 1) people with or without previous SARS-CoV-2 infection who 2) receive no, one or two vaccine injections.
|Table 5. Vaccination after previous SARS-CoV-2 infection|
|First dose of vaccine||Second dose of vaccine||Immunology|
|2||No||Yes||No||Protection starting around two weeks after the first injection. In one study, 92% of vaccinees (n = 475) had detectable anti-SARS-CoV-2 spike IgG three weeks after the first dose of BioNTech/Pfizer (Abu Jabal 2021).|
|3||No||Yes||Yes||Excellent protection (Dagan 2021).|
|4||Yes||No||No||(Some) protection against future SARS-CoV-2 infection, possibly even against variant strains such as B.1.1.7 and B.1.351 (Reynolds 2021), but protection probably not as good as in Scenario 3.|
|5||Yes||Yes||No||Rapid antibody response after one dose of either the BioNTech/Pfizer or the Moderna vaccine. Probably even better protection than in Scenario 3. A previous SARS-CoV-2 infection is analogous to immune priming – and a single vaccine dose acts as booster injection (Krammer 2021, Abu Jabal 2021, Saadat 2021, Manisty 2021, Goel 2021, Reynolds 2021), even in nursing home residents (Blain 2021).|
|6||Yes||Yes||Yes||After a previous SARS-CoV-2 infection, a second vaccine injection would seem to offer no additional protection (Goel 2021). Give the second injection to another person.|
In summary, people with prior SARS-CoV-2 infections
- Benefit from vaccination and should always be vaccinated
- Should probably receive only one dose of vaccine
- To make this dose available for another individual
- To avoid adverse events from the second dose. People with pre-existing immunity may experience systemic side effects such as fatigue, headache, chills, muscle pain, fever, and joint pain with considerably higher frequency than people without pre-existing immunity (Krammer 2021).
It will be interesting to monitor immunity to natural infection and following vaccination over time and show whether differences in vaccine immune response between previously SARS-CoV-2 infected or SARS-CoV-2 naïve individuals are maintained over time.
The debate about whether delaying the second booster vaccine dose is a risk – “extended prime-boost interval” strategy chosen by the UK to vaccinate a higher percentage of the population quicker and to maximize the number of people who would be partially protected from hospitalization and death – may be about to be settled. In a study of 175 people who were aged over 80 and living independently and who received the BioNTech/Pfizer vaccine, peak antibody levels were 3.5 times higher in those who received the booster dose 12 weeks after the first dose when compared to those who received it after 3 weeks (Parry 2021 – PR1, PR2). Further studies will have to show whether these findings can be repeated in younger people and whether the enhanced immune responses seen after an extended prime-boost interval will help sustain immunity over the longer term.
The Com-COV trial compares the four possible prime-boost combinations of the BioNTech/Pfizer vaccine and the AstraZeneca vaccine. The preliminary reactogenicity data show that among the participants who received the boost vaccine 28 days after the first dose, both heterologous vaccine schedules (BioNTech/Pfizer + AstraZeneca or AstraZeneca + BioNTech/Pfizer) induced greater systemic reactogenicity following the boost dose than homologous schedules (BioNTech/Pfizer + BioNTech/Pfizer or AstraZeneca + AstraZeneca); this was accompanied by more frequent use of paracetamol (see Table 6) (Shaw 2021). Most of this increase in reactogenicity was observed in the 48 h after the second dose. The authors of the study suggest that routine prophylactic use of paracetamol could help mitigate these effects. They also note that the participants in this trial were aged 50 years and older and that reactogenicity could be higher in younger individuals. Data about the primary immunological outcome are expected in June.
|Table 6. Feverishness* and paracetamol use after the booster dose in homologous and heterologous vaccine schedules|
|Prime/Boost (n)||Feverishness||Paracetamol use|
|BioNTech/Pfizer + BioNTech/Pfizer||118/117||21%||41%|
|AstraZeneca + AstraZeneca||115/112||10%||36%|
|AstraZeneca + BioNTech/Pfizer||114/110||34%||57%|
|BioNTech/Pfizer + AstraZeneca||115/114||41%||60%|
* Defined as a self-reported feeling of feverishness. Similar increases were observed for chills, fatigue, malaise, headache, joint and muscle ache.
The Spanish CombivacS study reported similar results. The study enrolled 673 volunteers who had received a first dose of the AstraZeneca vaccine. After 8 to 12 weeks, 441 individuals received the BioNTech/Pfizer vaccine for their second dose and 232 received a second AstraZeneca injection. In the BioNTech/Pfizer group, the neutralizing antibody titers rose seven-fold, as compared with three-fold in the AstraZeneca group (ISCIII 20210518). Less than 2% of study participants reported severe side effects, mostly headaches, general malaise and muscle pain.
In the future, such a vaccination strategy, also known as ‘heterologous prime and boost’, may simplify vaccination campaigns in countries with fluctuating vaccine supplies.
Preliminary data suggest that vaccinating 82% of a vulnerable nursing home population – while continuing to use face masks and other infection-control measures! – may be highly protective for the remaining 18% of unvaccinated residents (see Table 7). The study included 22,232 residents of 280 nursing homes across 21 US states, 18,242 (82%) of whom received at least one dose of mRNA vaccine (80.4% BioNTech/Pfizer, 19.6% Moderna) and 13,048 of these (71.5%) also received the second dose (White 2021). Most infections were asymptomatic, both in vaccinated and unvaccinated residents.
|Table 7. Incident SARS-CoV-2 infection among 3990 unvaccinated nursing home residents|
|Total||Asymptomatic SARS-CoV-2 infection||Symptomatic SARS-CoV-2 infection||Percent of infected residents who were asymptomatic|
|at 0-14 days*||173 (4.3%)||115 (2.9%)||58 (1.5%)||66.5|
|at 15-28 days*||69 (1.7%)||42 (1.1%)||27 (0.7%)||60.9|
|at 29-42 days*||16 (0.4%)||13 (0.3%)||3 (0.1%)||81.2|
|at > 42 days||12 (0.3%)||10 (0.3%)||2 (0.1%)||83.3|
* After first vaccination at the nursing home
In November 2020, the German company BioNTech and the New York-based Pfizer made history by presenting data which indicated that their vaccine tozinameran (formerly BNT162b2; trade name: Comirnaty™) had an extraordinary efficacy of over 90%. Four months later, these results were reproduced in a spectacular real-life analysis of almost 1.2 million people in Israel. The estimated effectiveness of the BioNTech/Pfizer vaccine after the second dose was 92% for documented infection, 94% for symptomatic COVID-19, 87% for hospitalization, and 92% for severe COVID-19 (Table 8) (Dagan 2021). The vaccine has gained full approval or authorization for emergency use (people 16 years of age) in more than 100 countries. In May, Canada and the US authorized the vaccine for children aged 12 to 15 (Health Canada 20210505, Wallace 2021).
|Table 8. Effectiveness of the BioNTech/Pfizer vaccine in Israel (2 x 596,618 persons) (Dagan 2021)|
|14 through 20 days after the first dose||21 through 28 days after the first dose||7 days after the second dose and later|
The BioNTech/Pfizer vaccine is a lipid nanoparticle–formulated (Pardi 2015) nucleoside-modified RNA vaccine (Karikó 2008; see also Karikó 2005 + Karikó 2012 + Karikó by Wired; Karikó by The New York Times) that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full length spike protein (Wrapp 2020). A Phase III trial demonstrated that two 30 μg doses given three weeks apart conferred 95% protection against COVID-19 in persons 16 years of age or older (Polack 2020). Of 170 confirmed COVID-19 cases, 162 occurred in the placebo group and 8 in the vaccine group. Efficacy was consistent across age, gender, race and ethnicity. In particular, the observed efficacy in adults over 65 years of age was above 94%. Safety over a median of 2 months was similar to that of other viral vaccines.
Researchers involved in the development of tozinameran had previously published Phase I safety and immunogenicity data (Walsh 2020). Two 30 μg doses had been shown to elicit high SARS-CoV-2 neutralizing antibody titers and robust antigen-specific CD8+ and Th1-type CD4+ T cell responses (Sahin 2020, Mulligan 2020).
Administration of the BioNTech/Pfizer vaccine swiftly started in many countries. On 31 December, WHO listed the Comirnaty COVID-19 mRNA vaccine for emergency use, making the BioNTech/Pfizer vaccine the first to receive emergency validation from WHO (WHO 20201231). Countries that do not have the means to rigorously assess the efficacy and safety of vaccines could now take advantage of the WHO EV and begin rolling out their vaccination programs.
Unopened thawed BioNTech/Pfizer vials can be stored at 2-8°C (i.e., in a normal fridge after taking out of deepfreeze conditions) for up to 31 days (EMA 20210517).
The BioNTech/Pfizer vaccine is effective against the B.1.1.7 variant – as a matter of fact, B.1.1.7 was the dominant lineage in Israel when the vaccination campaign started that would later provide the data for the Dagan study. The vaccine has also now been shown to be effective against B.1.351 (first detected in South Africa). In Qatar, in a real-world test, the effectiveness against any B.1.351 infection was 75%, approximately 20 percentage points lower than the effectiveness reported in studies from Israel (Dagan 2021, Haas 2021); however, effectiveness against severe, critical, or fatal disease was well over 90% (Abu-Raddad 2021).
Preliminary in vitro data had already suggested that the SARS-CoV-2 vaccines would retain activity against the B.1.351 (first detected in South Africa) and P.1 (Brazil) (Liu Y 2021, Lustig 2021). Individuals with prior infection showed excellent T cell immunity, antibody secreting memory B cells and neutralizing antibodies effective against B.1.1.7 and B.1.351 (Reynolds 2021). Other variants such as B.1.526 (New York), B.1.429 (California), and B.1.1.7+E484K (England) also seem to remain susceptible to neutralizing antibodies elicited by the BioNTech/Pfizer vaccine (Liu Y 2021b).
For the B.1.617 variant first identified in India (Vaidyanathan 2021), in vitro studies showed that B.1.617 evaded antibodies induced by infection (15 ICU COVID-19 patients) or vaccination (15 recipients of the BioNTech/Pfizer vaccine), although to a moderate degree (Hoffmann 2021). In another study, samples from convalescent patients and from individuals vaccinated with the the BioNTech/Pfizer or Moderna vaccines still had neutralizing activity against B.1.617.1 (although the variant was 7 times more resistant to neutralization) (Edara 2021). One B.1617 mutation, P681R, favored syncytium formation, potentially contributing to the increased pathogenesis observed in hamsters and contributing to the rapid spread of B.1.617 (Ferreira 2021).
The variant B.1.617.2 (a sub-lineage of B.1.617) is now considered a variant of concern (Public Health England 20210507, Public Health England 20210513, NYTimes 20210510), on par with B.1.1.7, B.1.351 and P.1. It seems to be at least as transmissible as B.1.1.7. In the UK, 3424 cases had been genomically confirmed by May 19, both imported and domesticallyacquired (Public Health England 20210507, Wise 20210521). Find a metaphor of an immunological B.1.671 landscape of hilly savannah with some distant mountains, featuring antelopes, hyenas and lions, at Tang J 2021.
As of now, the only side effect of concern seems to be an anaphylactic reaction which occurs very rarely (< 1:100,000) within minutes after receiving the vaccine. For a detailed discussion, see page 22.
Other side effects. Data on local and systemic reactions were collected with electronic diaries from participants in a reactogenicity subset of 8183 participants for 7 days after each vaccination. Local and systemic adverse events were reported more often by younger vaccine recipients (16 to 55 years of age) than by older vaccine recipients (older than 55 years of age) and more often after dose 2 than dose 1. Apart from pain at the injection site, the most commonly reported systemic events were fatigue and headache (see Tables 9 and 10). Most local and systemic reactions occur within the first 1 to 2 days after the injection and resolve within days. In some patients, axillary lymphadenopathy might indicate a robust vaccine-elicited immune response; it generally resolves within 10 days.
In comparison to these normal events, the incidence of serious adverse events was similar for tozinameran and placebo (0.6% and 0.5%, respectively).
|Table 9 – The BioNTech/Pfizer vaccine (Comirnaty™, Tozinameran; formerly BNT162b2): local and systemic reactions reported after the second injection of tozinameran or placebo (age group: 16-55 years) (FDA briefing document). See also Figure 2 of the paper by Polack et al.|
|Pain at injection site||78%||12%|
|Table 10 – The BioNTech/Pfizer vaccine (Comirnaty™, Tozinameran; formerly BNT162b2): severe local and systemic reactions reported after the second injection of tozinameran or placebo (age group: 16-55 years) (FDA briefing document).|
|Pain at injection site||1.2%||0%|
COVID-19-vaccination–related adenopathy may sometimes be indistinguishable from malignant nodal involvement and must be excluded in patients with manifest or suspected cancer (Becker 2021, Tu W 2021). In one study, among 169 vacinees who were scanned a median of 52 days after the second vaccine dose, 29% had positive axillary uptake 7–10 weeks after second vaccination, divided to 42%, 31%, 25% and 19% on 7th, 8th, 9th and 10th weeks respectively (Eshet 2021).
In May 2021, the FDA authorized the BioNTech/Pfizer vaccine for adolescents 12 to 15 years of age after a Phase III trial had demonstrated 100% efficacy and robust antibody responses. Among 2260 adolescents enrolled in the United States, there were 18 cases of COVID-19 in the placebo group versus none in the vaccinated group (FDA 20210510). The safety profile was identical to adults, with slightly less reactions than adults. Children 12 to 15 years of age had almost twice the amount of antibodies than adults (Wallace 2021). This expansion of the emergency use authorization (EUA) will allow US middle school-aged students to get vaccinated before the beginning of the next school year.
A global Phase I/II/III seamless trial to evaluate the safety, tolerability, and immunogenicity of the BioNTech/Pfizer vaccine in children 6 months to 11 years of age is under way. The trial will study three age groups: children aged 5 to 11 years, 2 to 5 years, and 6 months to 2 years (Pfizer 20210331). Results from this trial are expected in July for children five to twelve years old and in September for younger children. The evaluation of the trials is expected to take four to six weeks.
In February 2021, Pfizer and BioNTech registered a Phase II/III trial to evaluate the safety, tolerability, and immunogenicity of their vaccine in approximately 4000 healthy pregnant women 18 years of age or older vaccinated at 24 to 34 weeks’ gestation (NCT04754594). In the meantime, the CDC recommends that pregnant women who become eligible may choose to get vaccinated (CDC 20210305).
BioNTech and Pfizer have begun studying the safety and immunogenicity of a third dose of their vaccine to understand if a booster is sufficient to provide immunity against the new SARS-CoV-2 variants (Pfizer 20210225). In addition, the companies are planning a clinical study to evaluate a variant-specific vaccine with a modified mRNA sequence based on the B.1.351 lineage, first identified in South Africa.
1,800,000,000 BioNTech/Pfizer doses. EU Commission President Ursula von der Leyen announces a €30+ billion contract for the purchase of 900 million doses of the BioNTech/Pfizer vaccine plus an option for another 900 million doses to be delivered by 2023. The contract includes agreements to adapt the vaccine to new virus variants and to assure production in the EU, both of the vaccine and of essential components (Reuters 20210508).
In early February – after press releases, an emergency use authorization and the start of mass vaccinations – finally, the science behind the Moderna vaccine mRNA-1273 was published in an academic paper (Baden 2021). The Moderna vaccine has more than 90% efficacy at preventing COVID-19 illness, including severe disease. Moderate-to-severe systemic side effects, such as fatigue, myalgia, arthralgia, and headache, were noted in about 50% of participants in the mRNA-1273 group after the second dose. These side effects were transient, starting about 15 hours after vaccination and resolving in most participants by day 2, without sequelae. Antibodies elicited by the vaccine have been shown to persist through 6 months after the second dose (Doria-Rose 2021) – and will probably persist much longer.
The study by Baden et al. is the equivalent of the Polack study for the BioNTech/Pfizer vaccine. As of this writing (26 April), there is no real-world huge-scale data for the Moderna vaccine comparable to the data presented in the Dagan study for hundreds of thousand of individuals who received the BioNTech/Pfizer vaccine.
mRNA-1273, developed by Moderna, is a lipid nanoparticle–encapsulated nucleoside-modified messenger RNA (mRNA)–based vaccine that encodes the SARS-CoV-2 spike (S) glycoprotein stabilized in its prefusion conformation. The vaccine was approved on the basis of data from a Phase III trial which demonstrated that 100 μg taken four weeks apart conferred 94.5% protection against COVID-19 in persons 16 years of age or older (FDA EUA). Of 95 confirmed COVID-19 cases, 90 occurred in the placebo group and 5 in the vaccine group. Subgroup analyses of the primary efficacy endpoint showed similar efficacy point estimates across age groups, genders, racial and ethnic groups, and participants with medical co-morbidities associated with high risk of severe COVID-19.
Previous studies had demonstrated that mRNA-1273 induced potent neutralizing antibody responses (Korber 2020, Widge 2020, Anderson 2020) to SARS-CoV-2 as well as CD8+ T cell responses, and protects against SARS-CoV-2 infection in mice (Corbett 2020) and non-human primates (Corbett 2020b). In early clinical trials, mRNA-1273 induced anti–SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified (Jackson 2020). Check also this article at https://www.nytimes.com/interactive/2020/health/moderna-covid-19-vaccine.html.
There are to date no population-wide studies to assess the efficacy of the Moderna vaccine against the new SARS-CoV-2 variants B.1.1.7, B.1.351, P.1, B.1.429 and B.1.427.
In a neutralizing study of serum specimens obtained from 14 convalescent persons and from 49 recipients of the Moderna and the Novavax vaccine, B.1.429 (“California”) was approximately 2 to 3 times less sensitive to neutralization by convalescent serum and by serum samples obtained from vaccinated persons than the historical variant (Shen 2021). B.1.351 (“South Africa”) was approximately 9 to 14 times less sensitive.
As for now, the only side effect of concern seems to be an anaphylactic reaction which occurs very rarely (< 1:100,000) within minutes after receiving the vaccine. For a detailed discussion, see page 22.
A short discussion of other side effects:
- Side effects were transient, starting about 15 hours after vaccination and resolving in most participants by day 2, without sequelae (Baden 2020; see also Tables 11 and 12).
- With the exception of more frequent, generally mild to moderate reactogenicity in participants < 65 years of age, the safety profile of mRNA-1273 was generally similar across age groups, genders, ethnic and racial groups, and participants with or without medical co-morbidities.
- Several participants reported injection site reactions after day 7 that were characterized by erythema, induration, and often pruritis. Consultation with a dermatopathologist suggested that these were most likely dermal hypersensitivity reactions and were unlikely to represent a long-term safety concern.
- The rate of serious adverse events (SAEs) was low, and similar in both vaccine and placebo groups (around 1%). The most common SAEs in the vaccine group which were numerically higher than the placebo group were myocardial infarction (0.03%), cholecystitis (0.02%), and nephrolithiasis (0.02%), although the small numbers of cases of these events do not suggest a causal relationship (FDA Briefing). The most common SAEs in the placebo arm which were numerically higher than the vaccine arm, aside from COVID-19 (0.1%), were pneumonia (0.05%) and pulmonary embolism (0.03%). The incidence of serious adverse events was similar in the vaccine and placebo groups.
- There were three reports of facial paralysis (Bell’s palsy) in the vaccine group and one in the placebo group. There is insufficient information to determine a causal relationship with the vaccine.
|Table 11 – mRNA-1273: local and systemic reactions after the second injection of mRNA-1273 or placebo (18-64 years) (FDA Briefing).|
|Pain at injection site||90%||19%|
|Table 12 – mRNA-1273: severe local and systemic reactions after the second injection of mRNA-1273 or placebo (18-64 years) (FDA Briefing).|
|Pain at injection site||4.6%||0.2%|
With the Moderna vaccine (but not with the BioNTech vaccine), delayed localized cutaneous reactions near the injection site – pruritic, painful, and with edematous pink plaques (“COVID arm”) – have been described. They appear in a median of 7 days (range: 2-12 days) after the injection (Johnston 2021, n = 16). More than 70% of those who had a reaction to the first vaccine dose developed a similar reaction after the booster dose, generally sooner. Clinical and histopathologic findings suggest a self-limited delayed hypersensitivity reaction which is not a contraindication to subsequent vaccination.
In April, Moderna announced that a Phase II/III study of mRNA-1273 in adolescents ages 12-17 is fully enrolled with approximately 3000 participants in the US (Moderna 20210413). Results are expected by summer.
Another trial, a Phase II/III study of mRNA-1273 in children ages 6 months-11 years is currently enrolling in the US and Canada (target: 6750 participants) (Moderna 20210413). In Part 1 of this two-part, dose escalation study, children ages 2 years to less than 12 years will receive 50 μg or 100 μg. Children less than 2 years will receive 25 μg, 50 μg or 100 μg.
Moderna has recently published a pre-print describing two updated versions of its vaccine: 1) mRNA-1273.351 which encodes for the S protein found in the B.1.351 lineage and 2) mRNA-1273.211 which comprises a 1:1 mix of mRNA-1273 and mRNA-1273.351. In Balb/c mice, both mRNA-1273.351 and mRNA-1273.211 increased neutralizing titers against against the B.1.351 variant first identified in South Africa (Wu K 2021). Both mRNA-1273.351 and mRNA-1273.211 are now being evaluated in pre-clinical challenge models and in Phase I/II clinical studies.
Moderna has also started a Phase I study to assess the safety and immunogenicity of mRNA-1283, a potential refrigerator stable mRNA vaccine that would simplify distribution and administration (Moderna 20210315). In future studies, mRNA-1283 could be evaluated for use as a booster dose for previously vaccinated or seropositive individuals.
Moderna is currently investigating various booster options for its mRNA-1273 vaccine:
- A single half-strength (50 µg) booster dose of the first-generation ‘standard’ mRNA-1273
- mRNA-1273.351, a second-generation vaccine candidate targeting the B.1.351 variant first detected (fdi) in South Africa
- mRNA-1273.211, a multivalent vaccine candidate which combines first generation mRNA-1273 and mRNA-1273.351 in a single vaccine
Initial data from a Phase II study would suggest that that a single 50 µg dose of mRNA-1273 or mRNA-1273.351 given as a booster approximately 6 to 8 months after the primary vaccination series increased neutralizing antibody titer responses against B.1.351 (fdi South Africa) and P.1 (fdi Brazil) (Moderna 20210505). A booster dose of mRNA-1273.351 achieved higher neutralizing antibody titers against B.1.351 than a booster dose of mRNA-1273. Adverse events following the third booster injection were generally comparable to those observed after the second dose of mRNA-1273 in previously reported Phase II and Phase III studies.
The development of the AstraZeneca vaccine Vaxzevria™ (formerly AZD1222, ChAdOx1 nCoV-19), developed by University of Oxford/AstraZeneca, has been plagued by turbid data, contract negotiations with EU, supply shortfalls and, lately, by a link to fatal venous sinus thromboses especially in younger vaccinees. In the US, a company press release about a 32,000-person study in the US, Peru and Chile (NCT D8110C00001) suggested a 76% efficacy against symptomatic SARS-CoV-2 infection occurring 15 days or more after receiving two doses given four weeks apart (AstraZeneca 20210325). This would be higher than the 59.5% reduction of symptomatic COVID-19 cases which was the basis for the authorization of use in the European Union (EMA 20210129).
The AstraZeneca vaccine uses replication-deficient chimpanzee adenovirus vector ChAdOx1, which contains the full-length, unmodified spike protein of SARS-CoV-2. Researchers involved in the development of ChAdOx1 nCoV-19 had previously published results from a Phase I/II trial showing that in ChAdOx1 vaccine recipients, T cell responses peaked on day 14, anti-spike IgG responses rose by day 28, and neutralizing antibody responses against SARS-CoV-2 were detected in > 90%. Adverse events such as fatigue, headache, and local tenderness commonly occurred, but there were no serious adverse events (Folegatti 2020). A multiplex cytokine profiling and intracellular cytokine staining analysis demonstrated that ChAdOx1 nCoV-19 vaccination induces a predominantly Th1-type response (Ewer 2020). In a Phase II/III trial ChAdOx1 nCoV-19 appeared to be better tolerated in older adults than in younger adults and had similar immunogenicity across all age groups after a booster dose (Ramasamy 2020, Andrew 2020). Finally, in December, the results from four randomized studies showed that ChAdOx1 had an efficacy of 62-90% (Voysey 2020, Knoll 2020). Public funding could have accounted for well over 90% of the funding towards the research and development of chimpanzee adenovirus-vectored vaccine (ChAdOx) technology at the University of Oxford for over two decades and, lately, of the Oxford-AstraZeneca vaccine (Cross 2021).
On December 30, UK regulatory authorities approved the vaccine (GOV.UK 20201230), followed a month later by the European Union (EMA 20210129). In February, WHO granted Emergency Use Listing (EUL) for active immunisation to prevent COVID-19 in individuals 18 years of age and older, including those over 65 (AstraZeneca 20210215). In March, COVAX began delivering millions of doses of the vaccine to 142 low- and middle-income countries as part of the effort to bring broad and equitable access to the vaccine (AstraZeneca 20210302). The first shipments were dispatched to Ghana, Cote D’Ivoire, the Philippines, Indonesia, Fiji, Mongolia and Moldova.
After a possible link between the AstraZeneca vaccine and rare, but life-threatening thromboses together with thrombocytopenia (vaccine-induced immune thrombotic thrombocytopenia, VITT; see page 13), it is unclear if the vaccine will be approved by the FDA. If it is approved, it is unclear if it will be used in the US – the country has plenty of alternative vaccines. On 26 April, a senior US administration official was quoted saying that there could be “up to 60 million doses of the AstraZeneca vaccine available to be shared with other countries in the next two months” (Collins 2021). In the European Union, some countries like Denmark have stopped using the AstraZeneca vaccine. The European Union has not canceled its existing orders of the AstraZeneca and Johnson & Johnson vaccines, but signaled it might not be going to be placing more (NYTimes 20210414). When future historians come to retell the story of the COVID-19 pandemic, they may observe that VITT helped settle the EU-UK dispute about insufficient AstraZeneca deliveries to the European Union.
B.1.1.7 In Phase II/III vaccine efficacy studies in the UK, clinical efficacy of the AstraZeneca vaccine against symptomatic SARS-CoV-2 infection was slightly lower for B.1.1.7 lineages than for for non-B.1.1.7 lineages (70.4% vs 81.5%, respectively) (Emary 2021).
B.1.351. The AstraZeneca vaccine performed poorly in South Africa, as it offered no protection against mild-moderate COVID-19 (Madhi 2021). In early February, South Africa stopped plans for a rollout of 1 million doses of the vaccine.
P.1. No data.
As for possibly life-threatening thromboses together with thrombocytopenia after the administration of the AstraZeneca vaccine (EMA 20210407), see page 13.
Apart from this unusual and rare adverse event, the AstraZeneca vaccine is generally well tolerated (EMA 20210218, page 125). The most frequently reported solicited local adverse events (AEs) after any dose were tenderness (75.3% vs 54.2% in subjects who received a meningococcal ACWY vaccine) and pain (54.2% vs 35.4% in control). Severe local reactions were experienced by 0.8% of subjects.
The most frequently reported solicited systemic AEs were fatigue (62.3% vs 48.0% in control) and headache (57.5% vs 42.4% in control); other frequently reported systemic solicited AEs were muscle pain (48.6%), and malaise (44.2%). Pyrexia was reported in 9.2% participants who received any dose of the vaccine (vs 0.5% in control). Most of the systemic AEs following injection of the vaccine were mild or moderate. However, 9.3% of subjects experienced grade 3 systemic adverse events (malaise, chills, feverishness, etc.) (EMA 20210218, page 133).
Solicited local and systemic AEs were generally milder after the second dose than after the first dose of the vaccine.
In February, the University of Oxford announced the launch of the first study to assess the safety and immune responses of the AstraZeneca vaccine in children and young adults aged 6-17 years (Oxford University 20210212). The single-blind, randomised Phase II trial was to enrol 300 volunteers (240 would have received the AstraZeneca vaccine and the remainder a control meningitis vaccine). In early April, Oxford University announced that it was suspending the trial while British regulators investigated a potential blood clot link in adults. With British regulators recommending young adults 18 to 29 years old to be vaccinated with the BioNTech/Pfizer or the Moderna vaccine, the future of the AstraZeneca trial in childen and young adults aged 6-17 years is uncertain.
In December, AstraZeneca and Gamaleya announced that they would combine their vaccines to see if the combination would deliver a stronger protection than either vaccine on its own. A Phase I trial was registered on Christmas Eve 2020.
AstraZeneca and Oxford University have started working on a 2nd generation of their vaccine which would be adapted to target SARS-CoV-2 variants with mutations similar to B.1.351 (Oxford University 20210207).
The future role of the AstraZeneca product in the global COVID vaccine landscape is uncertain.
On 21 April, weeks after being authorized to be used in the USA (FDA 20210226) and Europe (EMA 20210311), the safety and efficacy data for the Johnson & Johnson (J&J) vaccine Ad26.COV2.S were finally published in a scientific journal (Sadoff 2021b). In a Phase III trial, the vaccine protected 66% of recipients against moderate to severe–critical COVID-19 and 85% against severe–critical COVID-19 one month after vaccination. Vaccine recipients who had breakthrough COVID-19 reported fewer and less severe symptoms than placebo recipients with COVID-19, which suggests that illness is milder after vaccination.
Earlier, results of a Phase I study (n = 25) had indicated that a single immunization with Ad26.COV2.S induced rapid binding and neutralization antibody responses as well as cellular immune responses (Stephenson 2021). In a later analysis, a single dose of Ad26.COV2.S was shown to elicit a strong humoral response in a majority of vaccine recipients (neutralizing antibodies in more than 90% of the participants in all age groups) and increasing antibody titers during 71 days of follow-up after the first dose. After two weeks, CD4+ T cell responses were detected in 76 to 83% (low dose vs high dose) among the 18 to 55 years old and and in 60 to 67% among those 65 years of age or older (Sadoff 2021). The CD8+ T cell responses were robust, but lower among the older participants.
Ad26.COV2.S is a recombinant replication-incompetent adenovirus type 26 (Ad26) vector-based COVID-19 vaccine encoding a prefusion-stabilized SARS-CoV-2 spike immunogen (Bos 2020). Its potency in eliciting protective immunity against SARS-CoV-2 infection was demonstrated in a non-human primate challenge model (Mercado 2020). Ad26.COV2.S induced robust neutralizing antibody responses and provided complete protection against a SARS-CoV-2 challenge in five out of six rhesus macaques and near-complete protection in one out of six macaques.
On March 12, the World Health Organization issued an Emergency Use Listing to Johnson & Johnson, accelerating its adoption by more countries (J&J 20210312).
Ad26.COV2.S is developed by the Janssen Pharmaceutical Companies of Johnson & Johnson.
In South Africa, where the B.1.351 variant was already present at the time of the study, vaccine efficacy was 64% against moderate to severe–critical COVID-19 and and 82% against severe–critical COVID-19, one month after vaccination (Sadoff 2021b).
Cases of cerebral venous sinus thrombosis (CVST) concomitant with thrombocytopenia, first described for the AstraZeneca vaccine (see pages 13), have also been described after vaccination with the Johnson & Johnson vaccine (Muir 2021, Sadoff 2021, Shay 2021). On 20 April, the European Medicines Agency (EMA) found a ‘possible link’ between the Johnson & Johnson vaccine and thromboses ‘at unusual sites such as in veins in the brain (cerebral venous sinus thrombosis, CVST) and the abdomen (splanchnic vein thrombosis) and in arteries, together with low levels of blood platelets and sometimes bleeding’ (EMA 20210420). The cases reviewed were very similar to the cases that occurred with the COVID-19 vaccine developed by AstraZeneca, Vaxzevria. EMA also said the use of the Johnson & Johnson vaccine “at national level will take into account the pandemic situation and vaccine availability in individual Member States.”
On 23 April, the FDA and the CDC recommended resuming the use of the Johnson & Johnson vaccine (FDA 20210423) after a 10-day pause (FDA 20210413). The agencies used the pause to inform healthcare providers and clinicians of what they dubbed thrombosis-thrombocytopenia syndrome (TTS) and how to manage and recognize the adverse event. At that time, FDA and CDC were aware of 15 cases of TTS reported to the Vaccine Adverse Event Reporting system VAERS. All cases occurred in women between the ages of 18 and 59, with a median age of 37 years. Reports indicated symptom onset between 6 and 15 days after vaccination.
It has been suggested (Muir 2021) that the rare occurrence of vaccine-induced immune thrombotic thrombocytopenia could be related to adenoviral vector vaccines. This interpretation was swiftly contradicted by the manufacturer, pointing out the differences between the Johnson & Johnson and the AstraZeneca vaccine (Sadoff 2021).
Other adverse events. Apart from the very rare VITT/TTS events, the Johnson & Johnson vaccine is generally well tolerated (Shay 2021). The most frequent solicited adverse events (AEs) were fatigue, headache, myalgia, and injection site pain. The most frequent systemic AEs was fever. Systemic AEs were less common in participants 65 years of age or older than in those between the ages of 18 and 55 years (Sadoff 2021; see also FDA 20210226, page 39). The local and systemic reactions occurred on the day of immunization or the next day and generally resolved within 24 hours.
Vaccine providers should also be aware of anxiety-related events, including episodes of syncope which have been reported at a rate of 8.2 per 100,000 vaccinations with the Johnson & Johnson vaccine (for comparison: 0.05 per 100,000 influenza vaccines during the 2019/2020 season) (Hause 2021).
In February, the company launched a trial for pregnant women with 400 participants (NCT04765384).
In November 2020, Johnson & Johnson launched a second Phase III trial to evaluate the efficacy of two doses of Ad26.COV2.S in the prevention COVID-19, as compared to one dose of Ad26.COV2.S (NCT04614948).
The European Union has not canceled its existing orders of the Johnson & Johnson vaccine, but signaled it might not be going to be placing more (NYTimes 20210414).
On 2 May 2021, four vaccines were approved outside the EU and the US in more than 10 countries (Table 13):
- The Gamaleya vaccine. Trade name: Sputnik V™ (formerly known as Gam-COVID-Vac)
- The Sinopharm vaccine, also known as BBIBP-CorV
- The Sinovac vaccine. Trade name: CoronaVac™ (formerly known as PiCoVacc)
- The Bharat vaccine. Trade name: Covaxin™ (formerly known as known as BBV152)
|Table 13. Vaccines approved outside the EU and the US in more than 10 countries|
|Vaccine platform||Type of candidate vaccine||Doses||Schedule|
|2||Day 0 + 21|
|Sinopharm||Inactivated virus||Inactivated SARS-CoV-2 vaccine (Vero cell)||2||Day 0 + 21|
|Sinovac||Inactivated virus||SARS-CoV-2 vaccine (inactivated)||2||Day 0 + 14|
|Bharat||Inactivated virus||Whole Virion Inactivated SARS-CoV-2 Vaccine (BBV152)||2||Day 0 + 28|
Sputnik V (formerly known as Gam-COVID-Vac), developed by the Gamaleya Research Institute, is a combination of two genetically modified and replication-incompetent human common cold virus adenoviruses, Ad26 and Ad5, given 21 days apart, each carrying an S antigen of SARS-CoV-2. The administration of two different serotypes is expected to overcome any pre-existing adenovirus immunity (Lu S 2009, Barouch 2010). The vaccine can be stored at freezer temperatures of -18°C (0°F).
In early February 2021, preliminary results from an interim analysis of the Phase III Gam-COVID-Vac trial (n = 14,964 in the vaccine group and 4902 in the placebo group) were published in the Lancet. As for the primary outcome – the proportion of participants with PCR-confirmed COVID-19 – the trial reported an efficacy of 91.6% from 21 days after the first dose of the vaccine (on the day of dose 2). In the vaccine group, (16 (0.1%) participants had confirmed COVID-19, compared to 62 (1.3%) in the placebo group (Logunov 2021; see also the comment by Jones 2021). Most reported adverse events were mild (94%).
In a small study (n = 12), the vaccine has been reported to maintain neutralizing activity against B.1.1.7, with a moderate reduction against B.1.1.7 carrying the additional E484K (“Eek”) substitution. Against the B.1.351 variant (first detected in South Africa), as expected, only 1 out of 12 serum samples showed effective neutralization (Ikegame 2021).
Although the two-dose regimen with the Ad26 and Ad5 vectors is likely to remain the future standard for the Gamaleya vaccine, Gamaleya has started a single-dose trial with 110 participants (“Sputnik-Light”) (NCT04713488). The one-dose schedule could be proposed as a temporary solution for countries with high infection rates.
In December 2020, Gamaleya and AstraZeneca announced that they would combine their vaccines to test if the combination would deliver a stronger protection than either vaccine on its own (NCT04684446).
In March 2021, the European Medicines Agency (EMA) started a rolling review (EMA 20210304). In South America, on 26 April, Brazil’s health authority declared it would not recommend importing Gamaleya’s Sputnik V vaccine on grounds of “crucial questions” about safety and the manufacturing process (see the detailed discussion by Derek Lowe, 2021). On the same day, Brazil also announced that it had ordered 100 million doses of the BioNTech/Pfizer vaccine and 38 million doses of the Johnson & Johnson vaccine.
The hair-raising presidential approval in August 2020 before Phase III clinical trials had even begun, gave the vaccine a long-lasting credibility blow. The latest exercise in ridicule, claiming Sputnik to be ‘The first registered COVID-19 vaccine’, is equally embarassing.
CoronaVac™ (formerly PiCoVacc) is an inactivated virus vaccine developed by Sinovac Biotech, a private Chinese company. In Brazil, CoronaVac is being developed in partnership with the Butantan Institute. In macaques, the vaccine provided partial or complete protection against SARS-CoV-2 challenge (Gao 2020). In a Phase I/II trial, CoronaVac was well-tolerated and moderately immunogenic in healthy adults aged 18–59 years. Most adverse reactions were mild, the most common symptom being injection site pain (Zhang Y 2020). In July 2020, the Chinese government approved CoronaVac for emergency use. In January 2021, the government of São Paulo, Brazil, announced the overall effectiveness of the Sinovac vaccine to be 50% in a study of 12,508 Brazilian health professionals. On 6 February, Sinovac announced that CoronaVac had been approved by the Chinese authorities. CoronaVac can be transported and refrigerated at 2–8 °C (36–46 °F).
In a real-world study in Chile, CoronaVac was shown to be 67% effective in preventing symptomatic infections after 14 days of the second dose. CoronaVac was also 85% effective in preventing hospitalization, 89% effective in preventing intensive care unit admission and 80% effective in preventing COVID-19-related death (Vergara 2021). The study, presented on 16 April by Chile’s Health Ministry, covered 10.5 million people, including 2.5 million who had received both doses of the vaccine and 1.5 million who had received a single dose during February and March 2021. In another real-world study of 21,652 Brazilian healthcare workers vaccinated between 18 January and 16 February with two doses of CoronaVac, the estimated effectiveness 2 and 3 weeks after the 2nd dose was 50.7% and 51.8%, respectively (de Faria 2021). Among 142 analyzed samples, 67 (47%) were variants of concern, mostly the P.1 strain. The discrepancy between the results of the two aforementioned studies is being discussed. Possible explanations include different dominant strains (in Brazil P.1 and P.2); different study populations (more exposed healthcare workers in the Brazilian study?); or more or less rigorous standards for defining a ‘case’ in trial participants.
In the setting of epidemic P.1 transmission, administration of one dose of CoronaVac has recently been estimated to be at least 35% effective against symptomatic SARS-CoV-2 infection (Hitchings 2021). In an in vitro analysis of 25 post-CoronaVac vaccination serum samples, B.1.351 has been shown to be more resistant to neutralization (by a factor of 2.5 to 3.3) than B.1.1.7 or the wild-type virus (Wang GL 2021).
In January 2021, according to a report of The New York Times (Wee SL 2021), Sinovac had sold more than 300 million doses, mostly to low- and middle-income countries. The contrast between a vaccine distributed by the hundreds of millions (CNA, 20 April), and the lack of published scientific data is disconcerting.
By early May, the vaccine had been approved in more than 20 countries, but not by FDA, EMA, or the Japanese or the Australian systems. On 4 May, the European Medicines Agency (EMA) announced that it had started a rolling review (EMA 20210504).
BBIBP-CorV is an inactivated virus vaccine developed by Sinopharm and the Beijing Institute of Biological Products, China. On 30 December 2020, the company announced that the vaccine had an efficacy of 79%. A day later, China’s health authorities approved the vaccine for general use (Davidson 2020, Wee SL 2021). BBIBP-CorV can be transported and stored at normal refrigerated temperatures.
Six months earlier, in June 2020, a Cell paper reported that BBIBP-CorV induced high levels of neutralizing antibodies titers in mice, rats, guinea pigs, rabbits, and non-human primates (cynomolgus monkeys and rhesus macaques). In rhesus macaques, a two-dose immunization also provided protection against SARS-CoV-2 intratracheal challenge, without detectable antibody-dependent enhancement of infection (Wang H 2020). In October 2020, results of a Phase I/II study showed that BBIBP-CorV was safe and well-tolerated in two age groups (18–59 years and ≥ 60 years) (Xia S 2021). On day 42, humoral responses had been induced in all vaccine recipients.
The B.1.1.7 variant showed little resistance to the neutralizing activity of vaccinee serum of 25 people 2 to 3 weeks after the second dose of BBIBP-CorV (Wang GL 2021). As anticipated (Liu Y 2021, Wang P 2021), the results were different for B.1.351 – 20 out of 25 serum samples showed complete or partial loss of neutralization. Another small study seems to contradict these findings, reporting 12 serum samples from recipients of the BBIBP-CorV vaccine which largely preserved neutralization of B.1.351 (Huang B 2021).
Sinopharm has yet to publish detailed results of their Phase III trial in peer-reviewed journals. On 7 May, WHO listed the vaccine for emergency use in people 18 years of age and older, giving the green light for the Sinopharm vaccine to be rolled out globally (WHO 20210507). WHO’s Emergency Use Listing (EUL) is also a prerequisite for COVAX vaccine supply. As for now, the vaccine has been approved in more than 40 countries.
Covaxin™ (formerly known as BBV152), developed by Bharat Biotech (Bharat Biotech, India) in collaboration with the Indian Council of Medical Research and the National Institute of Virology, is a whole virion inactivated SARS-CoV-2 vaccine, adjuvanted with Algel-IMDG (an imidazoquinoline molecule which is a toll-like receptor (TLR) 7/8 agonist, chemisorbed on alum [Algel]) (Ganneru 2021). In Syrian hamsters, Covaxin induced a potent humoral immune response, led to early clearance from the lower respiratory tract and protected the animals from pneumonia (Mohandas 2021). In rhesus macaques, too, the vaccine induced a strong immune response and protected the monkeys from pneumonia after infection with SARS-CoV-2, with complete viral clearance in nasal swab specimens 7 days post-infection (Yadav 2021).
In a Phase I/II trial (n = 375), the overall incidence rate of local and systemic adverse events was 14%-21% which seems to be lower than the rates for SARS-CoV-2 vaccines produced with other platforms such as mRNA (BioNTech/Pfizer, Moderna) or vector technology (AstraZeneca, Johnson & Johnson, Gamaleya) (Ella 2021). In a subsequent Phase III trial (n = 380), neutralizing antibody titres were similar to a panel of convalescent serum samples (Ella 2021b). Covaxin has also been reported to induce Th1-biased antibody responses with an elevated IgG2a/IgG1 ratio and increased levels of SARS-CoV-2-specific IFN-γ+ CD4+ T lymphocyte response (Ganneru 2021).
On 3 January, the Drugs Controller General of India (DCGI) approved the emergency use of Covaxin, making it India’s first vaccine against the pandemic, even though Phase III safety and efficacy clinical trials had not been completed. At that time, 22,500 of the 25,800 participants in a Phase III trial had been vaccinated (CTRI/2020/11/028976). On 21 April, Bharat Biotech announced that the second interim analysis of the Phase III study demonstrated a 78% vaccine efficacy in mild, moderate, and severe COVID-19 disease and a 70% efficacy against asymptomatic COVID-19 infection (Bharat 20210421).
Bharat has yet to publish detailed results of their Phase III trial. As of 2 May, the vaccine has been approved in 14 countries.
- The Coronavirus Vaccine Tracker (Carl Zimmer, Jonathan Corum and Sui-Lee Wee) – Excellent overview of all vaccines in development, always up-to-date.
- How Nine Covid-19 Vaccines Work (Jonathan Corum and Carl Zimmer) – Almost 100 vaccines are in human trials. Find out how 9 of them work.
The Novavax vaccine ‘NVX-CoV2373’ is a recombinant “nanoparticle” vaccine (rSARS-CoV-2; sometimes also called a ‘protein subunit vaccine’) composed of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant. The vaccine is produced by creating insect-infecting baculoviruses containing a gene for a modified SARS-CoV-2 spike protein which infects moth cells (the fall armyworm, Spodoptera frugiperda) in 2000 liter bioreactors (Wadman 2020). After extraction and chromatographical purification of the spike proteins, mixing with lipid particles and further co-formulation with the saponin-based adjuvant Matrix-M1 (Bangaru 2020, Tian JH 2021), NVX-CoV2373 is stored and stable at 2°-8°C (36°-46°F).
An early analysis revealed that the full-length immunogen was locked in a prefusion conformation (Bangaru 2020) and binds with high affinity to the ACE2 receptor. Early preclinical studies in mice and baboons revealed strong B and T cell responses to NVX-CoV2373 with no evidence of vaccine-associated enhanced respiratory disease (VAERS) (Tian JH 2021). In macaques, prime and booster immunization protected against SARS-CoV-2 replication in the nose and lungs, with no detectable replicating virus (sgRNA) in either upper or lower respiratory tracks (Guebre-Xabier 2020). Importantly, the authors of this paper also noted an absence of pulmonary pathology in the vaccinated animals.
A small Phase I/II clinical trial (Australia, n = 131) showed that the vaccine induced immune responses that exceeded levels seen in COVID-19 patients (Keech 2020). After the second vaccination neutralizing antibody responses were comparable to those seen in convalescent patients hospitalized with COVID-19.
Preliminary results from a Phase III trial in the UK (15,000 adult participants, with 27% percent being older than 65) suggest that the vaccine, administered as two injections 3 weeks apart, might be 96% effective against mild, moderate and severe disease caused by the historical SARS-CoV-2 strain (Novavax 20210311). Against variant SARS-CoV-2 strains, the Novavax vaccine:
- Maintains its efficacy more or less against the B.1.1.7 variant (first detected in England): 86.3% (95% CI: 71.3, 93.5) (Novavax 20210311)
- Shows 50% to 60% efficacy against the B.1.351 variant (depending on HIV serostatus). In a Phase II trial in South Africa where most SARS-CoV-2 infections were caused by B.1.351 (Shinde 2021), efficacy was:
- 60.1% in HIV–negative participants
- 49.4% in HIV-positive participants
Of interest, in a preliminary efficacy analysis of the South African Phase II trial, the incidence of COVID-19 observed among participants who were SARS-CoV-2 seronegative at baseline was 5.3% (33 mild and 47 moderate cases among 1516 vaccinees), similar to the 5.2% incidence among SARS-CoV-2 seropositive vaccinees (14 mild and 21 moderate cases among 674 participants) (Shinde 2021), suggesting that “previous infection with historical viruses did not appear to reduce the risk of COVID-19 after subsequent infection with B.1.351 (Shinde 2021).
Small in vitro studies of serum specimens from vaccinees suggest that B.1.1.7 (the variant first identified in [fii] England) and B.1.429 (fii California) are only slightly less sensitive to neutralization than the historical strain, whereas B.1.351 (fii South Africa) was found to be 9 to 14 times less sensitive (Shen X 2021, Shen X 2021b).
In a Phase II study in South Africa, adverse events generally subsisted within three days. The most common solicited systemic adverse events after both doses were pain at the injection site (more than one third of all vaccinees), headache (20 to 25%), muscle pain (17 to 20%), and fatigue (12 to 16) (Shinde 2021).
The company has also expanded its Phase III trial to include up to 3000 children ages 12 to 17.
Novavax has started a rolling review process of NVX-CoV2373 vaccine candidate with EMA, FDA, MHRA and Health Canada. However, because of regulatory and manufacturing problems, the Novavax vaccine is not expected to be authorized before July 2021 (Thomas 2021), with production reaching a peak only at the end of the year or later. This delay will impact a recent partnership with Gavi to supply 1.1 billion doses of the vaccine to low- and middle-income countries (Novavax 20210506). In April, financial analysts anticipated $33 billion in total sales 2021–2027 (GlobalData 20210408). The discrepancy between this forecast and the paucity of published scientific data is disconcerting.
The Phase III PREVENT-19 trial (NCT04611802) in the US and Mexico was postponed several times as Novavax struggled to scale up its manufacturing capability.
Recently, the company announced that it would not be able to reach the initial production target of 150 million doses a month because of supply shortages including the bags used to grow the moth cells (Reuters 20210413).
In 34 years, Novavax has never won regulatory approval for any of a vaccine candidates.
The immediate prospects of the COVID-19 pandemic are excellent, good or undetermined – depending on where you live.
The immediate prospects seem to be excellent for Israel (Balicier 2021). Soon, 60% of the total population will be fully vaccinated (Figure 2, green dots) which corresponds to more than 85% of the adult population as a third of the population is less than 16 years old. At the end of April, four months after the beginning of the vaccination campaign, the vast majority of adults had been vaccinated (see Table 14).
|Table 14. Israel, percentage of adults having received the first vaccine dose (by age group, end of April 2021):|
Despite an almost fully open economy since 7 March, the number of new daily cases has steadily declined ever since (Figure 2, red dashed line). From the peak in mid-January, the number of daily new cases has fallen by 98%, the number of new critically ill patients by 93%, and the number of daily deaths by 87% (Figure 3). Of interest, this effect was achieved with 60% of the population vaccinated (not 70%, 80% or 90%!).
Israel was the theater of the pivotal Dagan study (Dagan 2021; see also Efficacy, page 7).
Figure 2. SARS-CoV-2 cases in Israel, 10 May 2021. Impact of mass vaccination on the pandemic. The rolling 7-day average of new SARS-CoV-2 cases is shown in red (left vertical axis), the rolling 7-day average of deaths as the solid black line (right vertical axis). The percentage of people that have received at least one vaccine dose is shown in dotted green. The percentage of people that have been fully vaccinated is shown in solid green. The evolution of daily new cases and deaths was influenced by lockdown measures, transmissibility of circulating viruses and the vaccination campaign.
Figure 3. Israel, 25 April 2021. After a massive vaccination campaign, the number of daily new cases fell by 98% (blue), the number of new critically ill patients by 97% (orange), and the number of daily deaths by 99% (green). Source and copyright: Eran Segal, 25 April, https://bit.ly/3nneHgN.
During the first 112 days (December 2020 through April 2021), Israel’s vaccination campaign has been estimated to have averted at least 150,000 SARS-CoV-2 infections, 17,000 severe and critical hospitalizations, and 5,000 deaths (91% of these averted among individuals ≥ 65 years of age) (Haas 2021b).
For the US, the prospects are good. Although some states saw increasing numbers of daily new cases in what could have been the beginning of a fourth wave, the impressive US vaccination campaign was able to control the epidemic. In May, some Americans started discovering pre-COVID-19 freedom. The new recommendations published on 13 May by the CDC (CDC 20210513):
- If you are fully vaccinated, you can resume activities that you did prior to the pandemic. In general, people are considered fully vaccinated:
- 2 weeks after their second dose in a 2-dose series, such as the Pfizer or Moderna vaccines, or
- 2 weeks after a single-dose vaccine, such as Johnson & Johnson’s Janssen vaccine
- Fully vaccinated people can resume activities without wearing a mask or physically distancing, except where required by federal, state, local, tribal, or territorial laws, rules, and regulations, including local business and workplace guidance.
- If you haven’t been vaccinated yet, find a vaccine.
Find more details at https://www.cdc.gov/coronavirus/2019-ncov/vaccines/fully-vaccinated.html.
The last obstacle before achieving community-wide immunity and a return to some pre-COVID-19 life? Vaccine hesitancy!
On 19 May, the French government ordered the progressive easing of restriction measures and – unknowingly? – an informative experiment: will an aggressive vaccination campaign at a time of relatively low vaccination coverage (only 15% of the population was fully vaccinated and an additional 17% had received the first vaccine dose) be sufficient to end the national epidemic? Or will there be a fourth wave, particularly among young, non-vaccinated people? For comparison, Israel opened most of its economy after a two-month lockdown on 7 March, when 57.1% and 43.8% of the population had received one or two doses, respectively (Figure 4). Les jeux ne sont pas encore faits.
Figure 4. France in May 2021. “Daily new confirmed COVID-19 cases per million people”. Published online at OurWorldInData.org – accessed 24 May 2021.
Figure 3 (see above) provides a glimpse of a world where SARS-CoV-2 is being kept in check. Over the next months, we will address the following questions:
- Are COVID vaccines effective in children from 6 months to 11 years of age?
- Can vaccine doses from different manufacturers be used? (First dose with vaccine A, second dose with vaccine B?) Preliminary data suggest that the second dose of heterologous vaccine schedules (BioNTech/Pfizer + AstraZeneca; or AstraZeneca + BioNTech/Pfizer) might induce more frequent, generally mild adverse events (Shaw 2021). Data about the primary immunological outcome are expected in June.
- Which percentage of vaccinated people will have symptomatic or asymptomatic SARS-CoV-2 infection within 6, 12, 18 or 24 months after vaccination?
- Do vaccines prevent long COVID in vaccinated people who develop symptomatic SARS-CoV-2 infection?
- Are fully vaccinated people less likely to transmit SARS-CoV-2 to others if they get infected?
- To what extent will the B.1.351 and P.1 variants escape vaccine-induced immunity? If yes, will ‘updated’ versions of existing vaccines, especially the mRNA vaccines, be available soon?
- Will the efficacy of these second-generation mRNA booster vaccines be diminished by ‘antigenic sin’? Probably not.
- Will these second-generation vaccines have acceptable side effects?
Two pieces of good news are coming in from the variants front. The BioNTech vaccine has been shown to be effective against B.1.351 (first detected in South Africa). In Qatar, in a real-world test, the effectiveness against any B.1.351 infection was 75%, approximately 20 percentage points lower than the effectiveness reported in studies from Israel (Dagan 2021, Haas 2021); however, effectiveness against severe, critical, or fatal disease was well over 90% (Abu-Raddad 2021). In vitro data had already suggested that the SARS-CoV-2 vaccines would retain activity against the B.1.351 (first detected in South Africa) and P.1 (Brazil) (Moyo-Gwete 2021, Liu Y 2021, Lustig 2021, Reynolds 2021).
In a more distant future, we will appreciate how SARS-CoV-2 contributed to advances in medicine. One of the first achievements could be a pan-coronavirus vaccine. Some ground-breaking research has recently been published. First, a characterization of almost 3000 S-reactive T cell clones from 34 COVID-19 individuals revealed an immunodominant S346-365 region within the receptor-binding domain (RBD) that is highly conserved among zoonotic and human sarbecoviruses, including SARS-CoV-2 and its variants of concern. The S346-365 region was recognized by 94% of individuals and by 33% of the clones (Low 2021). Second, the vaccination of macaques with a pan-coronavirus mRNA nanoparticle vaccine elicited cross-neutralizing antibody responses against batCoVs, SARS-CoV-1, SARS-CoV-2, and SARS-CoV-2 variants B.1.1.7, P.1, and B.1.351 (Saunders 2021). This is just the first glimpse of new and momentous developments to come.
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EMA 20210311. EMA recommends COVID-19 Vaccine Janssen for authorisation in the EU. European Medicines Agency 2021, published 11 March. Full text: https://www.ema.europa.eu/en/news/ema-recommends-covid-19-vaccine-janssen-authorisation-eu + https://www.ema.europa.eu/en/medicines/human/EPAR/covid-19-vaccine-janssen
EMA 20210407. AstraZeneca’s COVID-19 vaccine: EMA finds possible link to very rare cases of unusual blood clots with low blood platelets. EMA 2021, published 7 April. Full text: https://www.ema.europa.eu/en/news/astrazenecas-covid-19-vaccine-ema-finds-possible-link-very-rare-cases-unusual-blood-clots-low-blood
EMA 20210420. COVID-19 Vaccine Janssen: EMA finds possible link to very rare cases of unusual blood clots with low blood platelets. European Medicines Agency 2021, published 20 April. Full text: https://www.ema.europa.eu/en/news/covid-19-vaccine-janssen-ema-finds-possible-link-very-rare-cases-unusual-blood-clots-low-blood
EMA 20210423. AstraZeneca’s COVID-19 vaccine: benefits and risks in context. European Medicines Agency 2021, published 23 April (accessed 23 April). Full text: https://www.ema.europa.eu/en/news/astrazenecas-covid-19-vaccine-benefits-risks-context + Graphic representation of the findings: https://www.ema.europa.eu/documents/chmp-annex/annex-vaxzevria-art53-visual-risk-contextualisation_en.pdf
EMA 20210504. EMA starts rolling review of COVID-19 Vaccine (Vero Cell) Inactivated. European Medicines Agency 2021, 4 May 2021. Full text: https://www.ema.europa.eu/en/news/ema-starts-rolling-review-covid-19-vaccine-vero-cell-inactivated
EMA 20210517. More flexible storage conditions for BioNTech/Pfizer’s COVID-19 vaccine. European Medicines Agency 2021, published 17 May. Full text: https://www.ema.europa.eu/en/news/more-flexible-storage-conditions-biontechpfizers-covid-19-vaccine
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 The vast majority of mRNA vaccinees received two doses within the usual vaccination schedule (BioNTech/Pfizer: 21 + 4 days, Moderna: 28 + 2). Of those receiving the AstraZeneca vaccine none received the second dose.
 Serious adverse events are defined as requiring hospitalization, deemed life-threatening, or resulting in persistent or significant disability/incapacity, another medically important condition, or death. The terms serious and severe are NOT synonymous. The general term severe is often used to describe the intensity (severity) of a specific event; the event itself, however, may be of relatively minor medical significance (such as a Grade 3 headache). This is NOT the same as serious, which is based on patient/event outcome and is usually associated with events that pose a threat to a patient’s life or ability to function. A severe AE (Grade 3 or 4) is not necessarily serious.
 HIT is a progressive thrombotic condition which can cause venous and arterial thrombosis, typically during the second week after exposure to heparin, especially after cardiac and orthopedic procedures (Warkentin 2016).
 In a study by Krammer et al., a single dose of mRNA vaccine in people with a history of SARS-CoV-2 infection (n = 67) elicited post-vaccination antibody titers exceeded the median antibody titers measured in participants without pre-existing immunity after the second vaccine dose (n = 43) by more than a factor of 6 (Krammer 2021) (80% received the Pfizer vaccine and 20% the Moderna vaccine).
 Licensed protein-based vaccines include the hepatitis B vaccine licensed in 1986, a flu vaccine approved in 2013 and the human papillomavirus vaccine for the prevention of of cervical cancer.
 Among 2684 participants who were SARS-CoV-2-seronegative at baseline (94% of them were HIV-negative and 6% were HIV-positive), symptomatic COVID-19 was observed in 15 participants in the vaccine group and in 29 participants in the placebo group.