Vaccines

By Thomas Kamradt & Bernd Sebastian Kamps

Published 13 January 2021

Summary

As of 8 January, three vaccines had been approved in Europe and in the US: tozinameran (Comirnaty™) by BioNTech/Pfizer (formerly known as BNT162b2), mRNA-1273 by Moderna and ChAdOx1 nCoV-19 by University of Oxford/AstraZeneca. Adverse events such as pain at injection site, fatigue, headache, myalgia and fever were common, but serious adverse events were rare. All three vaccines seem to have a favorable safety profile.

Three other vaccine candidates have been approved (not by FDA or EMA) although data are incomplete or have not yet been published:

  • China: BBIBP-CorV (30 December), Sinopharm and the Beijing Institute of Biological Products
  • India: Covaxin (3 January), Bharat Biotech
  • Russia: Sputnik-V (28 December), Gamaleya Research Institute

In early January 2021, 63 vaccine candidates were in clinical development against SARS-CoV-2 and 172 in pre-clinical development.- The World Health Organization (WHO) maintains a twice-weekly updated working document that includes most vaccines in development (https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines; accessed 8 January).  SARS-CoV-2 vaccine development is a dynamic field (Slaoui 2020, Heaton 2020) which is inaugurating a new future of vaccine science (Ball 2020).

On 8 January 2021, almost 20 million people had received a SARS-CoV-2 vaccine, mostly in the US, China, Israel, England, the United Arab Emirates, and Russia (OurWorldInData.org). In most countries, an effect of mass vaccination in changing the pandemic is not expected to be measurable before the summer.


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Approved SARS-CoV-2 vaccines – An overview

In the preface to our November edition, we predicted that “massive nationwide vaccine campaigns would not be available until well into 2021 and that massive global vaccine campaigns were unlikely to have a more than marginal impact on the SARS-CoV-2 pandemic before 2022, if ever.” We were wrong. As of 8 January, three vaccines have been approved in Europe and the US: see above. In Phase III trials, tozinameran and mRNA-1273 had an efficacy of over 94% while ChAdOx1 nCoV-19 had an efficacy of 62-90%. The vaccines are be given in two doses three (nRNA-1273), four (tozinameran) or up to 12 weeks apart (ChAdOx1). Vaccinees will be protected from SARS-CoV-2 infection from about 7 days after the second injection; some protection, especially against severe COVID-19, is provided by the first injection.

 

Table 5.1. SARS-CoV-2 vaccines approved in Europe (EMA) and the US (FDA)  
Vaccine
Manufacturer
Trial Efficacy Storage Administration References
Tozinameran
(formerly: BNT162b2)Comirnaty™BioNTech & Pfizer
95% –70°C 2 injections
3 weeks apart
Polack 2020
Mulligan 2020FDA EUA
FDA briefing doc
Sponsor briefing docRecommendation for use
mRNA-1273

N.N.™

Moderna

94% –20°C 2 injections
4 weeks apart
Polack 2020
Jackson 2020FDA EUA
FDA briefing doc
Sponsor briefing docRecommendation for use
ChAdOx1 nCoV-19 (formerly: AZD1222)

N.N.™

Oxford University
& AstraZeneca

62-90% 2-8°C
(fridge)
2 injections up to 12 weeks apart Voysey 2020
Folegatti 2020MHRA Decision

 


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All three vaccines seem to have a favorable safety profile (see below). 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. Importantly, serious[1] side effects were equally rare in people who received the vaccine and those who received placebo (Polack 2020, Baden 2020). Cases of anaphylaxis are very rare and may occur in 1 of 100,000 vaccine recipients (see next paragraph). Vaccine recipients should be informed that side effects generally do not signal that the vaccine is unsafe but, on the contrary, that the immune system is mounting a defense response against future exposure to SARS-CoV-2. We will learn to accept fever and aches as signs that the vaccine works, in rare cases even bone, muscle aches and fever that might last 12 hours (Wadman 2020). Mild side effects? Not really side effects. Vaccine at work!

On December 8, 2020, within 24 hours after the start of the UK vaccination program, the program reported probable cases of anaphylaxis 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 after 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). 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, CDC20210106). 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: All other persons

Find detailed information about tozinameran, mRNA-1273 and ChAdOx1 nCOV-19 on page 7.

Dosing schedule

As mentioned above, the vaccines should be given in two doses three (nRNA-1273), four (tozinameran) or up to 12 weeks apart (ChAdOx1). In the current situation of scarce vaccine supply, the UK Joint Committee on Vaccination and Immunisation (JCVI) now recommends that vaccinating more people with the first dose of both the Oxford/AstraZeneca and the BioNTech/Pfizer vaccine should be prioritized above offering others their second dose (JCVI 2020), as this would provide the greatest public health benefits in the short term and save more lives. For the BioNTech/Pfizer vaccine, the second vaccine dose could be offered between 3 to 12 weeks after the first dose. For the University of Oxford/AstraZeneca vaccine, the second dose could be offered 4 to 12 weeks after the first dose. The UK has also just opened the way to offering a vaccine “mix” (first injection of a first vaccine, the second of another) in cases where the second dose of the same vaccine is not available at a vaccination center for one person. Similar recommendations of a maximum of 41 days between the first and the second dose have been issued in Germany.

Distribution

Access to a safe vaccine will be unequal, both within countries and between them. Within countries, health authorities have prepared strategic prioritization plans (Lipsitch 2020), offering vaccines first to healthcare workers and people at high risk of severe COVID-19; then maybe to those living in epidemiological hotspots; and, finally, to the rest of the population – if they want to get vaccinated (Schwartz 2020, Bingham 2020). Between countries, there is no doubt that those that produce vaccines will get the vaccine before countries that don’t and that countries paying more will get vaccines earlier. On 24 August 2020, wealthy countries had pre-ordered around two billion vaccine doses without knowing which one may prove effective (see an overview of the August situation in Callaway 2020). As it is not acceptable that low-risk people in wealthy countries get the vaccine while health care workers in low- and middle-income countries do not, GAVI, the Vaccine Alliance (a Geneva-based funder of vaccines for low-income countries), the Coalition for Epidemic Preparedness Innovation (CEPI[2]) and the World Health Organization have set up the COVID-19 Vaccines Global Access (COVAX) Facility (Kupferschmidt 20200728, Jeyanathan 2020). COVAX aims to accelerate the development and manufacture of COVID-19 vaccines, and to guarantee fair and equitable access for every country in the world by securing 2 billion vaccine doses which should be enough to protect high risk and vulnerable people, as well as frontline healthcare workers. One billion have already been reserved for 92 low- and middle-income countries (LMICS), which make up half the world’s population. All participating countries, regardless of income levels, will have equal access to these vaccines once they are developed. For lower-income nations who would otherwise be unable to afford these vaccines as well as a number of higher-income self-financing countries that have no bilateral deals with manufacturers, COVAX is quite literally a lifeline and the only viable way in which their citizens will get access to COVID-19 vaccines. South Africa and India have asked the World Trade Organization to temporarily suspend intellectual property rights so that COVID-19 vaccines and other new technologies are accessible for poor countries (Usher 2020).


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Impact on the Pandemic

The fact that hundreds of millions of people will receive a SARS-CoV-2 vaccine during the first months of 2021 will not end the COVID-19 pandemic (Editorial 20201218). An exception may be countries like Israel that are able to vaccinate more than 1% of their population per day. These situations will provide the answer to the Question of 2021: When and how will vaccine impact a local epidemic? Over the coming 10 weeks, it will be highly instructive to update the three curves in Figure 5.1.

Figure 5.1. SARS-CoV-2 cases in Israel. Impact of mass vaccination on the pandemic. The rolling 7-day average of new SARS-CoV-2 cases is shown in red circles (left vertical axis), the rolling 7-day average of deaths as a plain black line (right vertical axis). The percentage of people vaccinated is shown in green squares. Please remember that the country entered a third lockdown on 27 December. The evolution of daily new cases and deaths will be influenced both by the lockdown measures and the vaccination campaign.

 

Mutations and vaccine efficacy

Multiple SARS-CoV-2 variants are circulating globally (CDC 2021 V, CDC 2021 NCV, Kupferschmidt 20201220, Kupferschmidt 20201223). In the autumn of 2020, several new variants emerged, most notably:

  • In England the new B117 variant (also known as B.1.1.7, 20B/501Y.V1, or VOC 202012/01; ECDC 20201220a, ECDC 20201220b, Lauring 2021) emerged with an unusually large number of mutations. This variant has since been detected in numerous countries around the world (Callaway 2021).
  • In South Africa, another variant of SARS-CoV-2 (known as 20C/501Y.V2 or B.1.351 lineage) emerged independently of the B117 lineage. It does share some mutations with B117. Cases attributed to this variant have been detected outside of South Africa.

All variants have multiple mutations in the Spike protein which are involved in receptor binding (Wong AHM 2017, Kistler 2020). This viral evolution is a normal process (all coronaviruses undergo antigenic evolution that erodes neutralizing antibody immunity (Eguia 2020)) – and has recently been reproduced in vitro (Zahradnik 2020).

The epidemiological consequences of these new variants are currently not foreseeable (Tufekci 2020, Felter 2021). There is no evidence that they cause more severe illness or increased risk of death; however, they seem to have a substantial transmission advantage (up to +75%) (Public Health England 2020, Volz 2021, Leung 2021). Increased transmission will lead to more SARS-CoV-2 infections and might significantly increase the number of deaths over the coming months (Figure 5.2).

Figure 5.2. A more infectious virus could lead to many more deaths. Simplified, hypothetical scenario showing the number of new deaths every six days from three different virus strains, assuming each strain started from 10.000 infections. Source: Adam Kucharski, Associate Professor, London School of Hygiene and Tropical Medicine.

 

Preliminary results suggest that existing mRNA vaccines will maintain efficacy against variants that share the N501Y mutation (Xie X 2020). However, a recently published comprehensive map of all amino acid mutations to the SARS-CoV-2 spike receptor-binding domain (RBD) show that the site where mutations tend to have the largest effect on antibody-binding and neutralization is E484 (Greasey 2020). The E484K mutation, too, is present in several emerging SARS-CoV-2 lineages (Tegally 2020, Voloch 2020). Intense research is currently investigating vaccine efficacy against variants with multiple mutations; results are expected within weeks. If widely circulating SARS-CoV-2 variants are confirmed to elicit insufficient neutralizing antibody responses after vaccination, existing SARS-CoV-2 vaccines would require reformulating.

Prices

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:

  1. University of Oxford/AstraZeneca: €1.78 (£1.61)
  2. Sanofi/GSK: €7.56
  3. Johnson & Johnson: $8.50 (£6.30)
  4. CureVac: €10
  1. BioNTech/Pfizer: €12
  2. Moderna/NIAID: $18

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).

Questions

After the beginning of mass vaccinations, numerous questions remain (Polack 2020, Rubin 2020):

  • Will unexpected safety issues arise when the number grows to millions and possibly billions of people?
  • Will side effects emerge with longer follow-up?
  • What happens to the inevitable large number of recipients who miss their second dose?
  • How long will the vaccine remain effective? Are re-vaccinations needed at regular intervals or might immunity last for years (Dan 2021)?
  • Will the vaccines also reduce transmission of SARS-CoV-2 when vaccinated (and protected!) individuals will become infected?
  • What about people who were not represented in the recent Phase III trials, such as children, pregnant women, and immunocompromised patients of various sorts?
  • Will new SARS-CoV-2 mutations require regular vaccine ‘updates’?

Vaccines

Tozinameran

In November 2020, the German company BioNTech and the New York-based Pfizer made history by presenting data which indicated that their vaccine tozinameran (trade name: Comirnaty) had an extraordinary efficacy of over 90%. Tozinameran is a lipid nanoparticle–formulated (Pardi 2015), nucleoside-modified RNA vaccine (Karikó 2008; see also Karikó 2005 + Karikó 2012 + Wired) that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein (Wrapp 2020). The vaccine was approved on the basis of data from a Phase III trial which 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).

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 5.2 and 5.3).  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).

The major drawback of the BioNTech/Pfizer vaccine is its temperature sensitivity – it must be stored at –70º C (–94º F) while the Moderna/NIAID vaccine can be stored at –20 C (–4º F). In normal refrigerator conditions the BioNTech/Pfizer vaccine can be stored only up to 5 days and the Moderna/NIAID vaccine up to 30 days. In this regard, the University of Oxford/AstraZeneca vaccine presents an important advantage: it can be transported at a temperature between 2 and 8º C (36º F to 46°F) for at least six months and could be administered by physicians, pharmacists or in other already existing healthcare settings.

A press article narrates the background of the Pfizer vaccine development: https://www.nytimes.com/2020/11/21/us/politics/coronavirus-vaccine.html. 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 who do not have the means to rigorously assess the efficacy and safety of vaccines can now take advantage of the WHO EV and begin rolling out their vaccination programs.

 

Table 5.2 – Tozinameran (Comirnaty™): 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.
Tozinameran

(Comirnaty™,
formerly: BNT162b2)

Placebo
Pain at injection site 78% 12%
Fever 16% 0%
Fatigue 59% 23%
Headache 52% 24%
Chills 35% 4%
Myalgia 37% 8%
Arthralgia 22% 5%

 

Table 5.3 – Tozinameran (Comirnaty™): severe local and systemic reactions reported after the second injection of tozinameran or placebo (age group: 16-55 years) (FDA briefing document).
Tozinameran

(Comirnaty™,
formerly: BNT162b2)

Placebo
Pain at injection site 1,2% 0%
Fever >38.9° 1,2% 0,1%
Fatigue 4,6% 0,7%
Headache 3,2% 0,7%
Chills 2,1% 0%
Myalgia 2,2% 0,1%
Arthralgia 1,0% 0,2%

 

mRNA-1273

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 comorbidities associated with high risk of severe COVID-19. The vaccine might also prevent severe COVID-19 and prevent COVID-19 following the first dose, but available data for these outcomes were not sufficient to allow for any firm conclusions.

Researchers involved in the development of mRNA-1273 had previously 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, it induced anti–SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified (Jackson 2020). Check also this press article at https://www.nytimes.com/interactive/2020/health/moderna-covid-19-vaccine.html.

Side effects (adverse events):

  1. Side effects were more frequent after the second dose. After the second dose, moderate-to-severe systemic side effects, such as fatigue, headache, chills, myalgia, and arthralgia, were noted in about 50% of participants in the mRNA-1273 group. The majority of solicited systemic adverse events were grade 1 to grade 2 in severity. In the mRNA-1273 group, the most common grade 3 solicited systemic ARs after the second injection included fatigue, myalgia, headache, and arthralgia.
  2. These 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 5.4 and 5.5).
  3. 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, participants with or without medical comorbidities, and participants with or without evidence of prior SARS-CoV-2 infection at enrollment.
  4. 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.
  5. 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.
  6. Throughout the safety follow-up period, there were three reports of facial paralysis (Bell’s palsy) in the vaccine group and one in the placebo group. Currently available information is insufficient to determine a causal relationship with the vaccine.

 

Table 5.4 – mRNA-1273: local and systemic reactions after the second injection of mRNA-1273 or placebo (18-64 years) (FDA Briefing).
mRNA-1273 Placebo
Pain at injection site 90% 19%
Lymphadenopathy 16% 4%
Fever 17% 0%
Fatigue 68% 25%
Headache 63% 26%
Chills 48% 6%
Myalgia 61% 12%
Arthralgia 45% 11%

 

Table 5.5 – mRNA-1273: severe local and systemic reactions after the second injection of mRNA-1273 or placebo (18-64 years) (FDA Briefing).
mRNA-1273 Placebo
Pain at injection site 4,6% 0,2%
Lymphadenopathy 0,4% < 0,1%
Fever 1,6% < 0,1%
Fatigue 10,6% 0,8%
Headache 5,0% 1,2%
Chills 1,5% 0,1%
Myalgia 10,0% 0,4%
Arthralgia 5,8% 0,3%

 

ChAdOx1 nCoV-19

ChAdOx1 nCoV-19 (or AZD1222), developed by University of Oxford/AstraZeneca, uses replication-deficient chimpanzee adenovirus vector ChAdOx1, which contains the full-length, unmodified spike protein of SARS-CoV-2. On December 30, UK regulatory authorities approved the vaccine (GOV.UK 20201230). The vaccine was approved in India a few days later.

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 has similar immunogenicity across all age groups after a boost 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). Importantly, no hospitalizations or severe cases of the disease were reported in participants receiving the vaccine. ChAdOx1 nCoV-19 (AZD1222) needs only normal refrigeration at 2-8°C and is far cheaper than the mRNA vaccines Comirnaty (BioNTech/Pfizer) and mRNA-1273 (Moderna).

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.

In October, an ideal pandemic vaccine was defined as being acceptably safe for everyone, effective in inducing a durable protective immune response, rapidly scalable, stable at room temperature, single dose and cost effective (Bingham 2020). ChAdOx1 nCoV-19 fulfills these requirements. AstraZeneca will soon seek an Emergency Use Listing from the World Health Organization for an accelerated pathway to vaccine availability in low-income countries.

Vaccine platforms

mRNA vaccines

The recently approved mRNA vaccines – tozinameran (Comirnaty™, BioNtech/Pfizer) and mRNA-1273 (Moderna/NIAID) – use a lipid-based nanoparticle carrier system that facilitates in vivo delivery and prevents the rapid enzymatic degradation of mRNA. This carrier system is further stabilized by a polyethylene glycol (PEG) 2000 lipid conjugate. PEG 2000 prolongs the half-life of the vaccine by providing a hydrophilic layer to the lipid nanoparticle.

An mRNA vaccine is comparable to software code which instructs human cells (the ‘operating system’) to produce its own SARS-CoV-2 vaccine. Once introduced into a cell, the mRNA molecule is read by a ribosome and translated into SARS-CoV-2 spike proteins (see Figure 5.3) which, when released into the body, are recognized by the immune system as other and trigger an immune response (Walsh 2020). Another mRNA vaccine currently in Phase III is CvnCoV by CureVac (NCT04652102).

mRNA vaccines have the potential to be truly transformative (Abbasi 2020). BioNTech, Moderna, CureVac and GSK own nearly half of the mRNA vaccine patent applications (Martin 2020).

 

 

Figure 5.3. Ribosomes assemble protein molecules whose sequence is controlled by the sequence of messenger RNA molecules. The growing peptide chain (top left) will form the SARS-CoV-2 spike protein. TRNA: transfer RNA.

Replication-incompetent vectors

Another approach is to use recombinant viral vectors in which an antigen of the pathogenic virus is expressed. Such vaccines are typically based on another virus that has been engineered to express the spike protein and has been disabled from replication in vivo by the deletion of parts of its genome (Krammer 2020). The majority of these vaccines are based on adenovirus (AdV) vectors. The vectors usually show good stimulation of B cell and T cell responses; however, pre-existing anti-AdV immunity might partially neutralize a candidate vaccine’s immunogenicity (Zhu FC 2020b). Before 2020, the Ebola vaccine was the only approved vaccine based on this principle (Henao-Restrepo 2017).

Replication-incompetent vector vaccines (approved or in advanced Phase III development) are being developed/distributed by

Other vaccine platforms

The most traditional way to produce vaccines is the use of whole viruses, which are either attenuated or inactivated. Currently licensed examples include the vaccines against measles and yellow fever (attenuated virus) and influenza and polio (inactivated viruses). Two inactivated vaccines protected rhesus monkeys from SARS-CoV-2. The vaccines were well tolerated pre-clinically and no type 2 immunopathology was found in the lungs (see below: pathological immune responses) (Gao Q 2020, Wang H 2020). Inactivated vaccines (in advanced Phase III development) are being developed by

  • Sinopharm + Beijing Institute of Biological Products: BBIBP-CorV; page 16
  • Sinovac Biotech: CoronaVac – Zhang Y 2020, Gao 2020; page 16
  • Bharat Biotech: Covaxin – Ella 2020; page 16

Find an overview of other platforms used for SARS-CoV-2 vaccine development at Krammer 2020 (the letters in the brackets refer to Figure 3 of the review):

  • recombinant protein vaccines based on the spike protein (e), the RBD (f) or on virus-like particles (g); licensed examples include the vaccines against hepatitis B and human papilloma virus.
  • replication-competent vector vaccines (i)
  • inactivated virus vector vaccines that display the spike protein on their surface (j)
  • DNA vaccines (k)

Vaccine candidates in Phase III Trials

On 8 January 2021, 63 vaccine candidates were in clinical development against SARS-CoV-2 and 172 in pre-clinical development. The World Health Organization (WHO) maintains a twice-weekly updated working document that includes most of the vaccines in development (WHO Landscape 2020; accessed 8 January).

 

Table 1. Vaccines in Phase III trials*
Vaccine candidate
Developers
Vaccine platform Type of candidate vaccine Doses Schedule
BBIBP-CorV
Sinopharm + Beijing Institute of Biological Products
Inactivated virus Inactivated SARS-CoV-2 vaccine (Vero cell) 2 Day 0 + 21
CoronaVac
Sinovac Biotech

(Zhang Y 2020,
Gao 2020)
Inactivated virus SARS-CoV-2 vaccine (inactivated) 2 Day 0 + 14
Covaxin
Bharat Biotech
Inactivated virus Whole-Virion Inactivated SARS-CoV-2 Vaccine (BBV152) 2 Day 0 + 14
Sputnik V
Gamaleya Research Institute
(Logunov 2020, Bucci 2020)
Viral vector
(Non-replicating)
Adeno-based
(rAd26-S+rAd5-S)
2 Day 0 + 21
Ad26.COV2.S Janssen Pharmaceutical
(Mercado 2020)
Viral vector
(Non-replicating)
Ad26.COV2.S 1-2 Day 0 or Day 0 +56
CvnCoV
CureVac
(NCT04652102)
RNA based vaccine

 

CVnCoV

 

2 Day 0 + 28
Convidecia CanSino Biological Inc./Beijing Institute of Biotechnology

(Zhu FC 2020a, Zhu FC 2020b)

Viral vector
(Non-replicating)
Recombinant novel coronavirus vaccine (Adenovirus type 5 vector; formerly: CTII-nCoV) 1 Day 0
NVX-CoV2373
Novavax(Keech 2020)
Protein subunit SARS-CoV-2 rS/Matrix M1-Adjuvant (Full length recombinant SARS CoV-2 glycoprotein nanoparticle vaccine adjuvanted with Matrix M) 2 Day 0 + 21
N. N.
Sinopharm + Wuhan Institute of Biological Products(Xia S 2020)
Inactivated virus Inactivated SARS-CoV-2 vaccine (Vero cell) 2 Day 0 + 21
ZF2001
Anhui Zhifei Longcom + Chinese Academy of Sciences
(NCT04646590)
Protein subunit Recombinant SARS-CoV-2 vaccine (CHO Cell) 2-3 Day 0 + 28 or Day 0 + 28 + 56
CoVLP

Medicago

(Ward 2020, NCT04636697)

Virus like particle

 

Coronavirus-Like Particle COVID-19 (CoVLP)

 

2 Day 0 + 21
SCB-2019
Clover Biopharmaceuticals
(Press release, NCT04672395)
Protein subunit SCB-2019 + AS03 or CpG 1018 adjuvant plus Alum adjuvant  (Native like Trimeric subunit Spike Protein vaccine)

 

2 Day 0 + 21

* Source: WHO Landscape 2020

 

BBIBP-CorV (China)

BBIBP-CorV is an inactivated virus vaccine developed by Sinopharm and the Beijing Institute of Biological Products. On 30 December, Sinopharm announced that the vaccine had an efficacy of almost 80%. A day later, China’s health authorities approved the vaccine for general use on the population (31 December 2020: The Guardian, The New York Times). Outside China, the vaccine has been approved in the United Arab Emirates and Bahrain.

CoronaVac (China)

CoronaVac™ is an inactivated virus vaccine developed by Sinovac Biotech. In macaques, the vaccine provided partial or complete protection against a 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, with the most common symptom being injection-site pain (Zhang Y 2020). In July 2021, the Chinese government approved CoronaVac for emergency use; it is assumed that the vaccine has been offered to people in high-risk jobs, for example, medical workers and other public service personnel. In Brazil, CoronaVac is being developed in partnership with the Butantan Institute. On 12 January, the government of São Paulo, Brazil, announced the overall effectiveness of the vaccine to be 50.38%. The data was obtained with tests carried out on 12,508 volunteers in the country, all health professionals. According to a report of The New York Times (7 January), Sinovac had sold more than 300 million doses, mostly to low- and middle-income countries, accounting for about half of the total production.

Covaxin (India)

Covaxin (formerly known as BBV152), developed by Bharat Biotech (Bharat Biotech, Hyderabad) in collaboration with the Indian Council of Medical Research and the National Institute of Virology, is a whole-virion inactivated SARS-CoV-2 vaccine. In a Phase I/II trial, robust humoral and cell-mediated responses were observed in the Algel-IMDG recipients (Ella 2020). Pain at the injection site resolved spontaneously. The overall incidence rate of local and systemic adverse events in this study was 10%-20% which is lower than the rates for other SARS-CoV-2 vaccine platform candidates and comparable to the rates for other inactivated SARS-CoV-2 vaccine candidates. On 3 January, the Drugs Controller General of India (DCGI) approved the emergency use of Covaxin, making it India’s first vaccines against the pandemic. At that time, 22.500 of the 25.800 participants in a Phase III trial had been vaccinated (CTRI/2020/11/028976). Bharat has agreed on a partnership with Ocugen (Pennsylvania) to develop Covaxin for the United States market (Ocugen Press release).

Sputnik V (Russia)

Sputnik V (formerly known as Gam-COVID-Vac), developed by the Gamaleya Research Institute, is a combination of two adenoviruses, Ad5 and Ad26, each carrying an S antigen of the new coronavirus. In a December 14 press release, Gamaleya announced an efficacy of over 90% of their vaccine after analyzing 22.714 volunteers who had received the first dose of the vaccine or placebo. The Gamaleya vaccine candidate might also prevent severe COVID-19 – there were 20 severe cases of coronavirus infection among confirmed cases in the placebo group and no severe cases in the vaccine group. These findings need to be confirmed.

Gam-COVID-Vac still suffers a serious handicap – there are no substantial data published to date. The small Phase I/II trials presented only 38 people. In their recent press release, the researchers from Gamaleya still provide no information on outcomes by age group, and no data on safety. In a late-December tweet, Gamaleya announced an efficacy of over 90 percent in people over 60. Gamaleya’s hair-raising communication skills – a premature presidential fake approval, Phase I/II results, press releases and tweets – clearly need coaching.

In December, Gamaleya and AstraZeneca 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.

Wuhan Institute vaccine (China)

In addition to BBIBP-CorV (from the Beijing Institute of Biological Products), Sinopharm also began testing an inactivated virus vaccine developed by the Wuhan Institute of Biological Products. In an interim analysis of 2 randomized placebo-controlled trials (96 and 224 healthy adults) showed that the vaccine produced antibodies (Xia S 2020). With the success of BBIBP-CorV, the future of the Wuhan candidate is uncertain. No clinical data.

Convidecia (China)

Convidecia (formerly: CTII-nCoV), developed by CanSino Biologics in partnership with the Institute of Biology at the Chinese Academy of Military Medical Sciences, is based on an adenovirus called Ad5. Results from a Phase I safety trial on Convidecia were published in May (Zhu FC 2020a). In July, Phase II trials demonstrated that the vaccine produced significant neutralizing antibody responses to live SARS-CoV-2 (Zhu FC 2020b) and that over 90% of participants showed either cellular or humoral immune responses at day 28 post-vaccination (Zhu 2020). The authors found that older people had a significantly lower immune response, but higher tolerability. Pre-existing immunity to the Ad5 vector and increasing age might partially hamper the specific immune responses to vaccination, particularly for the humoral immune responses. Adverse events such as fever, fatigue, headache, or local site pain were comparable to the ChAdOx1 study above. On 25 June, the Chinese military approved the vaccine for a year as a “specially needed drug.” In November, the Chief Executive of CanSino Biologics said in an interview that about 40.000 to 50.000 people had received Convidecia. Since August, Phase III trials have been under way in Russia, Pakistan, Mexico and Chile.

CvnCoV (Germany)

In December 2020, CureVac launched a Phase III trial of its vaccine candidate CvnCoV which will recruit 36.500 volunteers (NCT04652102). The first efficacy data are expected in summer 2021. In a November 2020 press release, the company claimed that CVnCOV might be stable for at least three months at +5°C (+41°F) and up to 24 hours at room temperature. This might give the vaccine an advantage over other mRNA vaccines such as tozinameran or mRNA-1273. It will be interesting to follow a CureVac-Tesla collaboration on creating mRNA “micro-factories” deployed around the world to make billions of doses of the vaccine. No clinical data.

Ad26.COV2.S (Belgium/US)

Ad26.COV2.S, developed by Janssen Pharmaceutical Companies of Johnson & Johnson, 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. A Phase III trial studying a 1-dose regimen started in September 2020. In November, Johnson & Johnson announced that they were launching a second Phase III trial to test a two-dose regimen. No clinical data.

NVX-CoV2373 (US)

NVX-CoV2373, developed by Novavax, is a recombinant nanoparticle vaccine (rSARS-CoV-2) composed of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant (Keech 2020). In a Phase I/II trial, the vaccine induced levels of neutralizing antibodies that closely correlated with anti-spike IgG. After the second vaccination neutralizing antibody responses exceeded values seen in symptomatic COVID-19 outpatients and were of the magnitude seen in convalescent serum from hospitalized patients with COVID-19. Phase III trials are under way in Britain and in the US. In September, Novavax signed a deal with the Serum Institute of India to produce a minimum of one billion doses of its NVX-CoV2373, thereby doubling its potential COVID-19 vaccine manufacturing capacity to two billion doses annually. No clinical data.

CoVLP (Canada)

CoVLP, developed by Medicago, is a coronavirus-like particle COVID-19 vaccine candidate composed of recombinant spike (S) glycoprotein expressed as virus-like particles (VLPs). A Phase I study showed that when combined with an adjuvant made by GSK, the vaccine produced promising levels of antibodies. A Phase II/III trial investigating two doses 21 days apart began in November 2020 (NCT04636697). The trial aims at enrolling more than 30.000 participants. No clinical data.

ZF2001 (China)

ZF2001 is a recombinant subunit candidate vaccine produced by the Chinese company Anhui Zhifei Longcom and the Chinese Academy of Sciences. The vaccine is composed of the receptor-binding domain of the spike protein and an adjuvant. Phase III trials will enroll 29.000 adult volunteers (NCT04646590). Global trials are expected to begin in Uzbekistan, followed by trials in Indonesia, Pakistan and Ecuador. The company announced an annual production capacity of up to 300 million doses. No clinical data.

SCB-2019 (China)

SCB-2019, developed by Clover Biopharmaceuticals, China, is a recombinant subunit vaccine candidate administered with AS03 adjuvant. Clover has produced an S trimer subunit vaccine candidate that resembles the native trimeric viral spike. A Phase II/III trial investigating two doses 21 days apart was to start in December 2020 (NCT04672395). The trial aims at enrolling more than 34.000 participants. No clinical data.

Immunization fundamentals

The SARS-CoV-2 pandemic and the unprecedented research effort to develop multiple vaccines on different platforms is the perfect time for immunologists to be involved in designing the next generation of powerful immunogens (Pollard 2020, Dagotto 2020).

Recovery from infections often induces long-term and sometimes life-long immunity against the causative pathogen. After the resolution of the infection, immunological memory protects against re-infection and is mediated by specific antibodies and T cells.

In contrast, immunizations confer immunity without exposure to virulent pathogens. Immunization can be passive or active. In passive immunization protective antibodies are transferred from a donor into a recipient whereas active immunization induces a protective immune response in the recipient.

Passive immunization against SARS-CoV-2

Passive immunization against SARS-CoV-2 can be achieved with convalescent plasma or with neutralizing monoclonal antibodies.

Convalescent plasma

Treatment with human convalescent plasma (CP) is based on the assumption that protective antibodies against the causative pathogen are present in the blood of people who have overcome an infectious disease. For example, CP has been used to treat some infectious diseases such as Argentine hemorrhagic fever (Casadevall 2004). CP was also used to treat SARS patients in the 2002/2003 epidemic but not in controlled clinical studies; a later meta-analysis concluded that the treatment was probably safe and perhaps helpful (Mair-Jenkins 2015).

CP could become an option for prevention and treatment of COVID-19 disease when there are sufficient numbers of people who have recovered and can donate immunoglobulin-containing serum (Casadevall 2020). Antibodies that are found in CP are very stable. Pathogen inactivation (using psoralen and UV light) did not impair the stability and neutralizing capacity of SARS-CoV-2-specific antibodies that was also preserved at 100% when the plasma was shock frozen at −30°C after pathogen-inactivation or stored as liquid plasma for up to 9 days (Tonn 2020). However, in a recently published open label randomized controlled trial (the largest to date with results) 464 patients were assigned either to two doses of 200 mL CP or standard of care only. The result was sobering: progression to severe disease at 28 days after enrolment occurred in 44 (19%) participants in the CP arm and 41 (18%) in the control arm (Agarwal 2020).

The major caveat of CP is quantity and quality of antibody titers. In plasma from 149 patients collected on average 39 days after the onset of symptoms, neutralizing titers were extremely variable. Most plasma did not contain high levels of neutralizing activity (Robbiani 2020). There seems to be a correlation between serum neutralizing capacity and disease severity, suggesting that the collection of CP should be restricted to those with more severe symptoms (Chen 2020). Another, unintended, consequence of receiving CP may be that recipients will not develop their own immunity, putting them at risk for re-infection.

In addition, in light of the possibility of antibody-dependent disease enhancement (ADE), safety is still a hypothetical consideration in the ongoing CP trials. One study on macaques found that passive transfer of anti-SARS-CoV-S immunoglobulin from immunized monkeys into naïve recipients resulted in acute lung injury after infection. The proposed mechanism was a diversion of macrophage activation from wound healing to pro-inflammatory (Liu 2019). Enhanced lung-pathology upon antibody-transfer was also observed in a rabbit model of MERS (Houser 2017). In one case, the administration of convalescent plasma to MERS patients raised the possibility of acute lung injury (Chun 2016).

The future development of anti-SARS-CoV-2 convalescent plasma should take into account 1) the potential harms of the non-immune components of convalescent plasma (especially prothrombotic risks); 2) that only donor plasma with detectable titers of neutralizing antibodies be given to trial participants; 3) ensure double-blind designs with placebo controls as the gold standard for future trials; 4) preclude non-immune plasma as a control intervention, because of potential harms and availability of lower risk alternatives such as normal saline (Pathak 2020).

In early January, a randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against SARS-CoV-2 (n=160) found that severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and 25 of 80 patients (31%) who received placebo (Libster 2021). Find more information on CP in the Treatment chapter, page 309.

Monoclonal antibodies

The development of highly successful monoclonal antibody-based therapies for cancer and immune disorders has created a wealth of expertise and manufacturing capabilities (Biopharma 2020) and neutralizing monoclonal antibodies are now a plausible therapeutic option against infectious diseases (Marston 2018). Monoclonal antibodies against rabies virus and against the respiratory syncytial virus (RSV) are approved for the treatment of patients and other monoclonal antibodies are in advanced stages of clinical trials (Walker 2018). Both protective and pathogenic effects were observed (Wang Q 2016, Chen X 2020). The ‘COVID-19 antibodysphere’ features companies like Amgen, AstraZeneca, Vir, Regeneron, Lilly and Adagio (Biopharma 2020). However, the future role of monoclonal antibodies as a bridging solution before the general availability of vaccines and efficient antiviral drugs is unclear. These drugs are complex and expensive to produce, leaving people from poor countries locked out (Ledford 2020, Ledford 2020b) and fears have been voiced that they could split the world into the haves and have-nots, like many other drugs before (Cohen 2020). Fortunately, these fears may not materialize. As soon as the first truly effective antiviral drugs become available – as for HSV in 1981, HIV in 1996 and HCV in 2013 – there will be no need for monoclonal antibodies anymore.

In 2020, SARS-CoV-2 neutralizing human monoclonal antibodies were intensely studied (Robbiani 2020, Wec 2020, Ju B 2020, Cohen 2020) and it was shown that REGN-CoV-2, a cocktail of two antibodies, might preclude the appearance of escape mutants (Baum 2020) and decrease virus-induced pathological sequalae in rhesus macaques (Baum 2020b). In November, the FDA issued an emergency use authorization for bamlanivimab (see page 305) and later for the antibody cocktail casirivimab (REGN10933)/imdevimab (REGN10987) (see page 305) to be administered together for the treatment of mild to moderate COVID-19 in patients of 12 years of age or older (weighing at least 40 kilograms) who are at high risk for progressing to severe COVID-19 (65 years of age or older or certain chronic medical conditions. These antibodies are not authorized for patients who are hospitalized due to COVID-19 or require oxygen therapy due to COVID-19.  Find more details on monoclonal antibodies in the Treatment chapter, page 305.

Issues to address during vaccine development

Rarely, vaccines can enhance disease rather than protect from disease (Kim 1969, Openshaw 2001). Some vaccine candidates against SARS-CoV-1 or MERS-CoV have caused disease-intensifying immunopathological effects in some pre-clinical models. Reassuringly, at least in the short term, results from the Phase III trials did not show evidence of enhanced respiratory disease after infection (Polack 2020, Voysey 2020, Baden 2020). Antibody-dependent enhanced infections may be unlikely because coronavirus diseases in humans lack the clinical, epidemiological, biological, or pathological attributes of ADE disease exemplified by dengue viruses (DENV) (Halstead 2020). In contrast to DENV, SARS and MERS CoVs predominantly infect respiratory epithelium, not macrophages.

Immunization with recombinant SARS-CoV spike (S) -coding modified vaccinia virus Ankara (rMVA) causes hepatitis in ferrets.

Ferrets are susceptible to SARS-CoV and SARS-CoV-2 infections (Kim YI 2020). Weingartl et al. immunized ferrets with a recombinant modified vaccinia virus Ankara (rMVA), which encoded the SARS-CoV S protein (Weingartl 2004). After infection with the virus, high titers of neutralizing antibodies were detectable in the immunized animals. Nevertheless, the immunized infected ferrets developed severe hepatitis while the non-immunized did not (Weingartl 2004).

Type 2 immunopathology in the lungs of immunized mice

Bolles et al. (Bolles 2011) immunized mice with inactivated SARS-CoV with or without adjuvant. The vaccine protected young and old animals from morbidity and mortality after infection with high doses of virus. If the mice were infected with a heterologous virus strain, the immunized animals developed more pronounced inflammatory infiltrates and pulmonary eosinophilia than the non-immunized (Bolles 2011). These results were later confirmed by another working group (Tseng CT 2012). Eosinophilic lung infiltrates were also observed in mice after immunization with a recombinant baculovirus (S protein) or coronavirus-like particles (VLPs) that expressed SARS-CoV S protein. It is important to note that these are histopathological findings; the immunized mice still had reduced virus titers after infection (Tseng CT 2012, Lokugamage 2008). Nevertheless, the findings are worrying. They are similar to the histopathological changes seen in the 1960s in children who became ill after immunization with a vaccine against RSV (Castilow 2007). Pathological changes in the lungs and even pneumonia after infection with SARS-CoV were also observed in mice in other SARS-CoV vaccine candidates (Yasui 2008).

Similar findings have been reported for vaccine candidates for MERS-CoV. An inactivated MERS-CoV vaccine induced neutralizing antibodies in mice. Nevertheless, after infection, the immunized mice developed an increased type 2 pathology in the lungs with increased eosinophilic infiltrates and increased concentrations of IL-5 and IL-13 (Agrawal 2016). Recent studies suggest that the development of type 2 immunopathology can be influenced by the choice of appropriate adjuvants, e.g. TLR ligands, for inactivated viruses, or recombinant S protein can be avoided (Iwata-Yoshikawa 2014, Honda-Okubo 2015).

Overall, these findings are a clear indication that during the preclinical development of vaccines against SARS-CoV-2, an intensive search should be made for immunopathological changes in the lungs of the immunized animals. It is encouraging that many of the pre-clinical studies published to date on SARS-CoV-2 vaccine candidates explicitly indicate that such changes have been sought and not found.

Type 2 immunopathology in the lungs of immunized primates

In a recent study Chinese macaques were vaccinated with a modified vaccinia Ankara (MVA) virus encoding full-length SARS-CoV S glycoprotein (ADS-MVA) and challenged with SARS-CoV 8 weeks later (Liu 2019). Vaccination induced high levels of antibodies and reduced virus loads. However, the vaccinated monkeys had diffuse alveolar damage (DAD) (Liu 2019). These findings are similar to those of an earlier study in which macaques were immunized with inactivated SARS-CoV. Three monkeys were protected upon challenge whereas one macaque had lung pathology consistent with antibody-dependent disease enhancement (ADE) (Wang Q 2016). The authors suspect that only antibodies against certain SARS-CoV S epitopes induce the immunopathology. In the previously published SARS-CoV-2 vaccination studies in monkeys, no lung pathology was observed (Gao Q 2020, Wang H 2020, van Doremalen 2020).

Questions for the Future

Despite the rapid and massive roll-out of highly effective vaccines, some important questions remain unanswered.

Correlates of Protection

Knowledge about the immune responses against SARS-CoV-2 is growing rapidly (Vabret 2020); it seems clear that neutralizing antibodies against the S protein can mediate protection. SARS-CoV-2-specific T cells can also be present in people without detectable antibodies against SARS-CoV-2 (Braun 2020, Grifoni 2020, Sekine 2020). Preclinical studies on SARS (Li CK 2008) and MERS (Zhao J 2017) suggest that virus-specific CD4+ (Zhao J 2016) and CD8+ (Channappanavar 2014) T cells can be protective even in the absence of serologically detectable antibodies (Tang F 2011). A challenge still needing to be addressed is the fact that the elderly are most susceptible to the infection and carry a particularly high risk for severe or lethal disease. Due to immunosenescence, the elderly are notoriously difficult to immunize, requiring usually higher doses or particular immunization schemes in order to generate a protective immune response.

Longevity of the immunological memory against SARS-CoV-2

Ideally, a vaccine induces long-term immunity. In the context of the SARS-CoV-2 pandemic, we will remember that infections with common cold coronaviruses generate only a short-lived immunity. Experiments from the 1980s have shown that just one year after inoculation with coronavirus 229E, the majority of the test subjects could be infected again. They did have milder symptoms than non-inoculated subjects, so a certain protection was seen despite renewed infection (Callow 1990).

Experience from the 2002-2004 SARS-CoV(-1) outbreak, too, suggest that SARS-CoV-2 immune responses will be short-lived. Six years after having suffered SARS disease, antibodies to SARS-CoV were no longer detectable in 21/23 patients (Tang F 2011). In contrast, SARS-CoV-specific T cells were still detectable, which suggests the possibility that T cell memory against coronaviruses may be more long-lasting than serological memory (Tang F 2011). Similar findings have been described for the immune response after MERS disease (Zhao J 2017); however, there is currently no reliable knowledge about the longevity of T cell memory against SARS-CoV 2. There have been reports of renewed SARS-CoV-2 infections after surviving the first infection (To KK 2020).

After almost one year of research, the picture of immunological memory against SARS-CoV-2 is becoming clearer. The kinetics of the neutralizing antibody response to SARS-CoV-2 is typical of an acute viral infection where a peak response is detected 3–4 weeks post-infection, which then wanes (Seow 2020). More than 90% of of infected individuals with mild-to-moderate COVID-19 experience might develop robust IgG antibody responses against the viral spike protein and titers will be relatively stable for months Anti-spike binding titers correlate with neutralization of authentic SARS-CoV-2 (Gudbjartsson 2020, Wajnberg 2020, Alter 2020). Patients with a worse clinical classification may have higher neutralizing antibody titer (Wang X 2020).

However, asymptomatic individuals have a weaker immune response to SARS-CoV-2 infection than patients with severe COVID-19 (Long QX 2020) and humoral immunity against SARS-CoV-2 may not be long-lasting in this large group that composes the majority of infected persons (Ibarrondo 2020, Weis 2020). One group showed that in individuals who develop a low neutralizing antibody response (ID50 100–300), titers can return to baseline over a relatively short period, whereas those who develop a robust neutralizing antibody response maintain titers > 1,000 despite the initial decline (Seow 2020).

After Year 1 of the SARS-CoV-2 pandemic, we realize that although millions of people were infected during spring 2020, there is no sizeable epidemic of re-infections. This observation suggests that SARS-CoV-2 infection might confer a solid immunity. Recently, Shane Crotty, Alessandro Sette, Daniela Weiskopf, Jennifer Dan and colleagues have analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 188 COVID-19 cases, including 43 cases at > 6 months post-infection. The result: Spike-specific memory B cells were more abundant at 6 months than at 1 month post symptom onset. SARS-CoV-2-specific CD4+ T cells and CD8+ T cells declined with a half-life of 3-5 months (Dan 2020). These findings suggest that after SARS-CoV-2 infection (or after vaccination), the vast majority of people could be protected from severe COVID-19 for years.

Pre-existing immune responses against SARS-CoV-2

SARS-CoV-2-specific CD4+ and CD8+ T lymphocytes can be detected in around 20 to 100% of non-exposed healthy volunteers (Braun 2020, Grifoni 2020, Mateus 2020, Bacher 2020). It has been speculated that these cross-reactive T lymphocytes could be protective against SARS-CoV-2 or influence the course of the disease. As a matter of fact, it is known that cross-reactive T cells can influence the course of viral infections both positively and negatively (Ngono 2018). Antibodies that neutralize SARS-CoV-2 have also been detected in uninfected and non-exposed healthy volunteers (Ng KW 2020).

We might not rely on protection without exposure, though. In a recently published pre-print study from Rockefeller University, the authors measured neutralizing activity against SARS-CoV-2 in pre-pandemic sera from patients with prior PCR-confirmed seasonal coronavirus infection. While neutralizing activity against seasonal coronaviruses was detected in nearly all sera, cross-reactive neutralizing activity against SARS-CoV-2 was undetectable (Posten 2020). The authors conclude that while it is possible that there are rare instances of individuals possessing antibodies from prior seasonal HCoV infection who may be able to also target SARS-CoV-2 S, their data would argue against a broad role for pre-existing protective humoral immunity against SARS-CoV-2.

Recently, a provocative concept was introduced by Alexander Scheffold and colleagues. The authors propose the immunological age as an independent risk factor for developing severe COVID-19 (Bacher 2020). Their reasoning:

  1. Unexposed individuals harbor SARS-CoV-2-specific memory T cells with marginal cross-reactivity to common cold corona and other unrelated viruses.
  2. Low avidity pre-existing T cell memory negatively impacts on the T cell response against neoantigens such as SARS-CoV-2, which may predispose to developing inappropriate immune reactions especially in the elderly.

Find more about this topic in the 7th edition of COVID Reference.

Outlook

This rapid development of SARS-CoV-2 vaccines is the result of a massive global effort, including the parallelization of development and production steps that have traditionally been carried out sequentially (Lurie 2020), the knowledge generated in attempts to develop vaccines against SARS-CoV-1 and MERS-CoV, and innovative techniques (Hekele 2013) that were not available until recently. The speed of SARS-CoV-2 vaccine development was breathtaking. On 11 January 2020 Chinese researches published the sequence of the SARS-CoV-2 genome on the internet. Approximately 2 months later, on 16 March, an mRNA-based vaccine entered a Phase I clinical trial (Arnold 2020). Earlier work had identified the S protein of SARS-CoV and MERS-CoV as a suitable vaccine target. The S protein binds to its cellular receptor, ACE2, to infect human cells. With the sequencing of the genome of SARS-CoV-2, the high homology between the S proteins of the 3 viruses was known and a little later the interaction of SARS-CoV-2 with ACE was confirmed (Hoffmann 2020). A relevant target structure for immune responses was identified in record time.

In less than a year, we have characterized a novel illness, sequenced a new viral genome, developed diagnostics, produced treatment protocols, and established the efficacy of drugs and vaccines in randomized controlled trials (Editorial 20201121). More people will be able to get vaccinated more quickly than ever before. If we can achieve some kind of pre-COVID-19 ‘normalcy’ by 2022, it would be an historical feat remembered by generations.

Nobody should forget: vaccines are the most potent medical products of all time to prevent morbidity and mortality. Over the last two centuries, no other medical intervention has saved as many lives. Without vaccines, many of today’s anti-vaccine activists (Burki 2020) would not have been born (and maybe neither you nor me) because of lack of ancestors – one or more of them would have succumbed to infectious disease before reaching mating age. Vaccines train the body’s immune system to recognize and fight pathogens and on the next exposure to the pathogen, the immune system is ready to fight the invader off. The vaccination procedure is simple: introduce certain molecules from the pathogen into the body – the mass equivalent of a few grains of fine salt – and trigger an immune response. Vaccines are ‘elegant medicine’ – they prevent rather than treat a disease.

At the end of this COVID Year One, virology, biologic chemistry and immunology are the celebrated fields of medicine. Virology explores the structure and functioning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and, together with biologic chemistry, prepares the terrain for future drug development. In the meantime, immunology explores the virus-human interface and describes how the human body fights back and forms a memory after the first encounter with SARS-CoV-2: it examines why most people recover from the infection while a few die and other remain disabled; and it contributes to the understanding of the biological mechanisms that lead to illness and death. Why do older people die from COVID-19 while younger people don’t? Why are people with hypertension, diabetes or obesity at increased risk of severe COVID-19? Immunology also tries to elucidate the mystery of superspreader individuals, those few acutely SARS-CoV-2 infected people who are thought to be responsible for the vast majority of transmissions. Finally, immunology will spin out the most powerful antiviral weapon: vaccines.

For quite some time, the SARS-CoV-2 pandemic will continue to be a colossal challenge for healthcare systems and societies. It is also the time of the ‘Great Rehearsal’. By coordinating global resources and supra-national structures to react swiftly, science is currently creating the infrastructure to fight any other new and potentially far deadlier viral disease that emerges in the future. SARS-CoV-2 is not the last pathogen humanity will have to deal with in the 21st century and more enzootic viruses will jump from their animal reservoirs to humans. After this pandemic, hopefully we will be better prepared for future challenges, with new vaccine platforms that can be quickly adapted to newly emerging viral diseases. There is even a final twist to the unexpected events of 2020: the SARS-CoV-2 pandemic is opening up a new era of vaccine development. In 10 years we can expect to have a wide range of new and innovative vaccines (Dolgin 2021) we would not have dared to previously dream of.

[1] 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.

[2] The Coalition for Epidemic Preparedness Innovation (CEPI), an international nongovernmental organization funded by the Wellcome Trust, the Bill and Melinda Gates Foundation, the European Commission, and eight countries (Australia, Belgium, Canada, Ethiopia, Germany, Japan, Norway, and the United Kingdom), is supporting development of vaccines against five epidemic pathogens on the World Health Organization (WHO) priority list (Lurie 2020).

References

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By Thomas Kamradt &

Bernd Sebastian Kamps