Copy-editor: Rob Camp
Revised 2 May 2021
As of 26 April 2021, four COVID-19 vaccines have been approved or authorized for emergency use in the EU or in 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 vaccine candidates 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 historical 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 has been demonstrated as soon as two weeks after the first injection (Table 2; find more sub-population data at https://bit.ly/2PNPSOA).
|Table 2. Effectiveness of the BioNTech/Pfizer vaccine in Israel (2 x 596,618 person) (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 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 like France, Germany, Italy, and some US states where B.1.1.7 has become or is becoming the dominant strain.
Other Phase IV analyses confirm the efficacy of COVID-19 vaccines:
- 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 those ≥ 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 and 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 RNA vaccines) was observed as early as 12 days after a single 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. Early T cell and binding antibody responses, rather than either receptorblocking or virus neutralizing activity, might induce 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) (Table 2).
- 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).
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 and P.1
- 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
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 fetal loss, 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.
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 16). 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 this writing (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 have been 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).
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. Two new reports describe 14 recent French cases with a mean age of 62/63. Half of them were men (ANSM 20210416, 16 April; ANSM 20210423, 23 April).
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, a prothrombotic disorder caused by platelet-activating antibodies that recognize multi-molecular complexes between cationic PF4 and anionic heparin (Greinacher 2015). [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).] 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
A suspicion of VITT is confirmed by the presence of anti-PF4 antibodies (Juhl 2006, Selleng 2015) with an approved PF4 ELISA (see also Oldenburg 2021). Find a diagnostic algorithm and therapeutic strategies for the management of suspected VITT in Figure 1 (Greinacher 2021).
Figure 1. Potential diagnostic and therapeutic strategies for management of suspected vaccine-induced immune thrombotic thrombocytopenia. Shown is a decision tree for the evaluation and treatment of patients who have symptoms of thrombocytopenia or thrombosis within 20 days after receiving the ChAdOx1 nCov-19 vaccine and who have had no heparin exposure. The diagnostic and therapeutic strategies in such patients differ from those in patients with autoimmune heparin-induced thrombocytopenia (HIT).13 DIC denotes disseminated intravascular coagulation, INR international normalized ratio, PF4 platelet factor 4, and PTT partial thromboplastin time. Source: Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. N Engl J Med. 2021 Apr 9. Full text: https://doi.org/10.1056/NEJMoa2104840. Copyright: The New England Journal of Medicine 2021.
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 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 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 30 years to be offered an alternative COVID-19 vaccine, if available (JCVI 20210407) (unless they have underlying health conditions that put them at higher risk of severe COVID-19 disease). Given the low mortality in people younger than 30 and those 30 to 39 years of age (< 1:10,000 and < 1:5,000, respectively; CDC 20210218, Levin 2020), some physicians, especially those in private practice, might feel more comfortable administering non-AstraZeneca vaccines even in those older than 30 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), medium (401 per 100,000 people) and high (886 per 100,000 people) (EMA 20210423). The following three figures show the 1) number of deaths (Figure 2), ICU admission (Figure 3) and hospitalizations (Figure 4) prevented and the 2) number of cases of thrombosis with thrombocytopenia (VITT) in a low infection rate scenario. Find 6 more figures for medium or high infection rate scenarios at https://covidreference.com/astrazeneca-vaccine-benefit-vs-harm.
Figure 2. Deaths prevented vs VITT. Weighing up the potential benefits and harms of the AstraZeneca vaccine in a low transmission rate scenario. From: AstraZeneca’s COVID-19 vaccine: benefits and risks in context. Medicines Agency (EMA) 2021, published 23 April (EMA 20210423)
ICU admissions prevented
Figure 3. ICU admissions prevented vs VITT. Weighing up the potential benefits and harms of the AstraZeneca vaccine in a low transmission rate scenario. From: AstraZeneca’s COVID-19 vaccine: benefits and risks in context. Medicines Agency (EMA) 2021, published 23 April (EMA 20210423)
Figure 4. Hospitalizations prevented vs VITT. Weighing up the potential benefits and harms of the AstraZeneca vaccine in a low transmission rate scenario. From: AstraZeneca’s COVID-19 vaccine: benefits and risks in context. Medicines Agency (EMA) 2021, published 23 April (EMA 20210423)
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 (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).
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. In summary, a relatively low number of cerebral sinus vein thromboses and splanchnic vein thromboses will reshape the landscape of COVID vaccines.
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). 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
Next pages: Vaccine overview, Single Vaccines and Outlook.
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 4) (Dagan 2021).
|Table 4. 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 Pfizer vaccine swiftly started in many countries. On 31 December, WHO listed the Comirnaty COVID-19 mRNA vaccine for emergency use, making the Pfizer/BioNTech 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.
A press article narrates the background of the Pfizer vaccine development: https://www.nytimes.com/2020/11/21/us/politics/coronavirus-vaccine.html.
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. Preliminary data suggests that the vaccines may also retain activity against the B.1.351 (first detected in South Africa) and P.1 (Brazil) (Liu Y 2021). Another paper reports that in 6 healthcare workers who had been infected with the original virus, a single dose of the BioNTech/Pfizer vaccine induced robust neutralizing antibody responses against all variants of concern, including B.1.351 (Lustig 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 16.
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 5 and 6). 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 5 – 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 6 – 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%|
In late March, Pfizer and BioNTech announced that their vaccine had demonstrated 100% efficacy and robust antibody responses in adolescents 12 to 15 years of age. The Phase III trial which had enrolled 2260 adolescents in the United States observed 18 cases of COVID-19 in the placebo group versus none in the vaccinated group (Pfizer 20210331). In the US, an emergency use authorization (EUA) by the FDA could arrive in time for vaccinating this age group before the 2021/2022 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 the second half of the year.
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.
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 16.
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 6 and 7).
- 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 7 – 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 8 – 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%|
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.
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 6), 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 6.
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 6), have also been described after vaccination with the Johnson & Johnson vaccine (Muir 2021, Sadoff 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. 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.
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 9):
- 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 9. 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.
As of 2 May, the vaccine has been approved in more than 20 countries, but not by FDA, EMA, or the Japanese or the Australian systems.
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. As of 2 May, 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).
Preliminary results suggest that Covaxin could be effective against B.1.1.7 (Sapkal 2021).
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 immediate prospects of the COVID-19 pandemic are grim, good or excellent – depending on where you live.
In India, several studies suggest high SARS-CoV-2 seroprevalence rates exceeding 40% in New Delhi and Mumbai (Chen X 2021), making some epidemiologists believe that in terms of new cases and deaths, “the worst is behind us” (cited in Mallapaty 20210318). Then, in early April, a second pandemic wave of unprecedented proportions took off (Figure 5). In 12 days, the COVID positivity rate in India doubled to 17%, in Delhi to 30%. Hospitals have been reported to be running out of oxygen and bodies are stacking up in morgues (Ellis-Petersen 2021, Safi 2021). Still in Delhi, two thirds of cases have been reported to be in people under 40 years old. Policital rallies without proper social distancing and religious festivals like the Kumbh Mela gathering which attracts tens of millions of people were not helpful in curbing the latest COVID-19 wave. The reasons for this unprecedented surge are as yet unclear (emergence of new [B.1.617] variants? rise in unrestricted social interactions? lack of preventive measures like hand washing, wearing masks and social distancing?) (Mallapaty 20210421).
Figure 5. US and India, April 2021. Source: Our World in Data – Johns Hopkins University CSSE COVID-19 Data.
For the US, the immediate prospects are good. Although some states saw increasing numbers of daily new cases in what could have been the beginning of a fourth wave (Figure 6), the impressive US vaccination campaign seems to be controlling the epidemic. Even Michigan seems to be coming out of the woods.
Figure 6. B.1.1.7 Spring wave in selected US states. To recalculate these values as the ‘cumulative 7-day rolling incidence per 100,000 people’, multiply the values by 7. Example: the April 7 value for Michigan, 70, is equivalent to a cumulative 7-day incidence of 490/100,000 people. Source and copyright: Financial Times 2021, accessed 24 April.
- Visit with other fully vaccinated people indoors without wearing masks or physical distancing
- Visit with unvaccinated people from a single household who are at low risk for severe COVID-19 disease indoors without wearing masks or physical distancing
- Refrain from quarantine and testing following a known exposure if asymptomatic
- Resume domestic travel and refrain from testing before or after travel or self-quarantine after travel.
- Refrain from testing before leaving the United States for international travel (unless required by the destination) and refrain from self-quarantine after arriving back in the United States.
The immediate prospects seem to be excellent for Israel. Soon, 60% of the total population will be fully vaccinated (Figure 7, green dots) which corresponds to more than 85% of the adult population as a third of the population is less than 16 years old. Despite an almost fully open economy since 7 March, the number of new daily cases has steadily declined ever since (Figure 7, 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 8). 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 1).
Figure 7. SARS-CoV-2 cases in Israel, 22 April 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 8. 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.
Figure 8 (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 16 years of age? (The first step seems to be done: a recent press release announced that the BioNTech/Pfizer vaccine was 100% effective in a Phase III trial of adolescents (n = 2260) 12 to 15 years of age [Pfizer-BioNTech 20210331]). Will AstraZeneca vaccine trials in children continue?
- Can vaccine doses from different manufacturers be used? (First dose with vaccine A, second dose with vaccine B?) There is no published data yet but from an immunological viewpoint, it is to be expected that combining different vaccines is safe and effective.
- 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?
- Will the Southern Hemisphere variants B.1.351 and P.1 escape vaccine-induced immunity? If yes: will ‘updated’ versions of existing vaccines, especially the mRNA vaccines, be available soon? Will new studies need to be done?
- Will the efficacy of these second-generation mRNA booster vaccines be diminished by ‘antigenic sin’?
- Will these second-generation vaccines have acceptable side effects?
Two pieces of good news are coming in from the variants front. First, in six HCW who had been infected with the original virus, one dose of the BioNTech/Pfizer vaccine induced robust neutralizing antibody responses against all variants of concern, including B.1.351 (Lustig 2021). Second, sera from B.1.351-infected patients have been shown to maintain good cross-reactivity against historical strains (viruses from the first wave) (Cele 2021) and would also seem to neutralize P.1 (Moyo-Gwete 2021). If these data are confirmed, vaccine manufacturers working on a B.1.351-adapted vaccine are on the right track.
* * *
This chapter is currently being revised and will soon be republished fully.
* * *
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 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.