The short version: Geert Vanden Bossche has recently published a letter in which he argues that the vaccination campaign against COVID-19 is going to precipitate a public health disaster because the vaccines will select for viral variants that can escape their protection and drive them towards higher virulence. His claims are speculative, he offers no evidence to support his arguments, and makes several comments which are blatantly incorrect. The core of his argument relies on the assumption that COVID-19 vaccines do not have a significant effect on transmission. This has been repeatedly confirmed to be false in multiple studies. Furthermore, even if his assumptions about the effects of the vaccine on transmission are true, his conclusions are incorrect based on established precedent from Marek’s disease, a viral illness of birds with a vaccine that does not strongly affect transmission- but it still shows meaningful public health benefits in the populations of chickens where it is used. The vaccines will absolutely be critical to ending the pandemic, and fortunately the modular nature of the technology allows for rapid reformulation and adjustment as necessary (and thus far, though precautions are being taken with novel variants to produce vaccines specific to their set of problematic mutations, there isn’t significant enough evidence to suggest that total reformulation of the vaccines is needed), but no issues raised in this letter warrant a re-evaluation of our current COVID-19 vaccination policy.

I won’t be addressing the contents of Dr. Vanden Bossche’s resume as it’s irrelevant to the fact that he is currently making unsupportable claims, but for those seeking a backgrounder on the subject, Dr. Iannelli has graciously obliged. I also won’t be linking to his original letter.

I’ll be blunt: there is very little within this letter that is even close to being correct, and there is almost no evidence presented to support any of its claims. I’ll now go through it point-by-point to explain where it’s wrong.

It's not exactly rocket science, it’s a basic principle taught in a student’s first vaccinology class: One shouldn’t use a prophylactic vaccine in populations exposed to high infectious pressure (which is now certainly the case as multiple highly infectious variants are currently circulating in many parts of the world).

There is no such principle. It in fact directly goes against current policies for responding to outbreaks of e.g. measles, mumps, meningococcal disease, etc. and more generally is directly at odds with the incredibly effective ring vaccination strategy.

To fully escape selective immune pressure exerted by vaccinal antibodies, Covid-19, a highly mutable virus, only needs to add another few mutations in its receptor-binding domain

COVID-19 is a clinical syndrome, and therefore incapable of mutating; the virus causing it is SARS-CoV-2.

This claim remains to be substantiated and in fact has considerable evidence against it. While it’s true that variants of concern demonstrate reduced antibody neutralization, we do not have an absolute correlate for which antibody levels would be protective and therefore the meaning of this is hard to determine. The antibody titers induced by the vaccines are MUCH higher than those seen with infection, and we see hallmarks of memory responses induced by these vaccines from even a single dose, meaning that even though there is a drop in neutralization, it may not mean a loss in protection. Novavax’s recent Phase 3 clinical trial did show reduced efficacy against B.1.351 which has a constellation of problematic mutations that manage to reduce antibody binding affinity and also increase affinity for ACE2, however the key point is that: no one in the vaccinated group developed severe disease. The simplest explanation I can propose for this is: there is no significant change to the T cell response with the variants in either recovered or vaccinated individuals and T cell responses are critical determinants of patient clinical course. Importantly, it is possible that vaccines may simply need a bit more time for high-affinity antibodies against the variants to be generated (see “affinity maturation”; also addressed in more detail in the context of HIV here). It is also worth noting that in studies examining the antibody responses to variants of concern, some individuals do already exhibit antibodies that cross-neutralize problematic strains at similar levels. Nonetheless, it is not as though we are sitting idle and allowing SARS-CoV-2 to accumulate escape mutations. For one thing, Moderna has completed enrollment of a phase 1 trial for a variant-specific mRNA vaccine targeting B.1.351 which bears a constellation of concerning mutations in its spike protein shown to dramatically reduce antibody binding. Evidence has already confirmed that antibodies against B.1.351 cross-neutralize with ancestral variants. Pfizer and Novavax are also working on updated vaccines against the variants of concern in case they may be needed. Critically, it would seem that immunocompromised individuals are critical in the evolution of problematic SARS-CoV-2 variants, and thus protecting them from infection is imperative (and a vaccination strategy -our current vaccination strategy- will play a key role in that, but I’ll revisit this shortly when discussing evidence for the effects of the vaccines on transmission).

Not only would people lose vaccine-mediated protection but also their precious, variant-nonspecific (!), innate immunity will be gone (this is because vaccinal antibodies outcompete natural antibodies for binding to Covid-19, even when their affinity for the viral variant is relatively low).

This is absolute, unvarnished nonsense. Bossche is referencing the production of natural IgM, which is generated by B1-B cells as a stopgap measure against infections until more potent responses can be initiated; these antibodies are polyreactive, nonspecific, and critically: constitutively produced. They are always present for as long as B1-B cells generating them live. IgM is pentameric and thus even though it has lower affinity than antibodies that have had the opportunity to evolve superior binding affinity, it can compensate with the fact that it has 10 binding sites instead of 2. However, IgG antibodies bear many of the same effector functions (actually, they tend to be better at many of them, as Table 10.27 shows) and they can diffuse into extravascular sites unlike IgM. Principally, antibodies against SARS-CoV-2 could be of value if they are neutralizing. Bossche presents no evidence to support that natural IgM is neutralizing (rather than just binding) SARS-CoV-2.

Bossche subsequently goes on to define:

*NACs: Natural asymptomatic carriers ; refers to subjects who do not develop any clinical symptoms at all, or develop at most mild (involving upper respiratory airways only), after PRIMARY CoV infection

**nonNACs: Relates to subjects who develop severe Covid-19 symptoms after PRIMARY infection

Firstly, an asymptomatic patient does not develop mild symptoms. This is not what asymptomatic means. An asymptomatic patient does not develop ANY symptoms. There is another term -paucisymptomatic- which describes individuals who develop only mild disease.

He then argues that in NACs, the reason for their lack of progression to the disease state is a rapid NK cell response that clears the virus. This is possible, but he presents no evidence to support it. Current models attribute the lack of progression to (severe) disease in these patients to a rapid interferon response, and while interferon responses can promote NK cell activity to clear virally infected cells, the literature does not discuss a role for the cells, given that interferon can induce direct intracellular effectors that suppress viral replication and furthermore the presence of antibodies among asymptomatic individuals. Overexuberant NK cell responses are implicated in the development of severe COVID-19: afucosylated antibodies are extremely potent inducers of NK cell antibody-dependent cellular cytotoxicity (ADCC), and these are noted to be enriched in severe COVID-19. NK cell-mediated ADCC is extremely powerful for controlling viral infections, particularly before the adaptive immune system gets an opportunity to produce its effectors, and afucosylated antibodies are valuable players in that process, but the inflammation that results can be harmful to the health of the host if uncontrolled, such as if SARS-CoV-2 is given an opportunity to replicate extensively in a host, as might be the case in an individual whose immune system has not been primed against the virus with vaccination.

He then commits an immunological faux pas so egregious that it genuinely shocks me where he shows a dendritic cell (DC) activating an NK cell via antigen presentation on an MHC class I protein. It is basically at this point that I cannot presume that this letter is written in good faith given Dr. Bossche’s background. This is absolutely not how NK cells work. For one thing, the presence of MHC class I protein on a cell indicates to an NK cell that no viral infection is present and functions as an inhibitory signal (indeed, it is a common feature that viruses suppress expression of MHC class I proteins on cells they infect because this prevents them from being recognized by cytotoxic T cells that can kill the cell they are relying on to replicate). For another, NK cells do not examine the contents of the antigen in the MHC binding cleft. They do not have T cell receptors (with the exception of iNKT cells) and therefore have no ability to do this. There ARE reciprocal NK cell-DC interactions where each supports the other (e.g. DCs may produce cytokines promoting the activation of NK cells and NK cell cytokines can promote DC maturation, and NK cells have been known to kill immature dendritic cells in the body) but the mechanism proposed here is overtly at odds with decades of immunology research.

Frankly, to focus on NK cells for a vaccine against an infectious disease is extremely unusual (they can be very important in cancer immunotherapy though). The goal of vaccines broadly is to elicit long-lived immunological memory against a particular infectious agent. NK cells are part of the innate immune system, and while they do exhibit epigenetic modifications after infection in what has been termed trained immunity, this is not the principle by which most vaccines work. Vaccines have to achieve robust activation of dendritic cells because they are key antigen presenting cells and they need to trigger generation of memory helper T cells, ideally T follicular helper cells, memory B cells, long-lived plasma cells, and potentially cytotoxic T cells (depending on the agent)- they act virtually independently of NK cells (though NK cells may play a supportive role through ADCC on challenge with the antigen).

It is very much downhill from here. While he does not use the term, the rest of the argument Bossche makes relies on a false assumption: currently available vaccines for COVID-19 are leaky vaccines. Correlates of vaccine-induced protection: methods and implications defines leaky vaccines as follows:

According to [the leaky vaccine model], the risk of infection/disease in all vaccinees is reduced (by VE %) compared to non-vaccinees, none of the vaccinees being fully protected.

The assumption that no vaccinee is totally or permanently protected implies one or both of the following:

i) No amount (titre) of the immune marker is totally protective or, if it is, no individual can maintain that titre for a long period (because of waning or transient immunosuppression);

ii) The degree of protection is a function of the level of the immune marker – the simplest explanation being that protection is a function of both the level of the immune marker and the challenge dose.

In other words, leaky vaccines are vaccines which are not able to significantly affect transmission of the pathogen. The critical question here is firstly: are COVID-19 vaccines leaky vaccines?

1. This study compared PCR positivity among asymptomatic individuals who had received an RNA vaccine to those who had not been vaccinated and found it was approximately 80% lower. This is a very strict bar and it likely underestimates the ability of the vaccines to reduce transmission, because PCR can detect as few as ~100 copies of viral RNA. SARS-CoV-2, being a coronavirus, likely requires several hundred viral copies to initiate productive infections from one person to the next. An asymptomatic individual who tests positive may not necessarily be contagious.

2. Novavax’s vaccine demonstrated sterilizing immunity (the virus failed to even initiate infection) in nonhuman primate studies.

3. ChAdOx-nCoV-2019 also showed significant reductions in PCR positivity among vaccinees compared with unvaccinated controls.

4. The SIREN study showed that Pfizer’s vaccine prevents infection with B.1.1.7 variants.

5. Pfizer’s vaccine was able to reduce viral load by a factor of about 4 among vaccinees compared with unvaccinated controls.

6. The Johnson and Johnson/Janssen vaccine showed significant reductions in PCR positivity among vaccinees compared with controls.

And so on. In short, nothing about the COVID-19 vaccines suggests that they are leaky.

For a moment though, let’s entertain the notion that the vaccines are leaky. In general, you would have a hard time identifying any human vaccine that could be called leaky (though emerging findings regarding influenza vaccines give hints that there may be a leaky vaccine effect involved, given their excellent efficacy among children, who are critical vectors, I am not so convinced- though if we do grant that they are leaky, this only serves to undermine Bossche’s argument). The classic example of a leaky vaccine is actually the one for Marek’s disease, caused by a herpesvirus that infects chicken and causes lymphoma among other illnesses. It has been observed that over time Marek’s disease virus has become more virulent, and this has been attributed classically to a leaky vaccine effect. Still, as Osterrieder et al write (emphasis mine):

Box 2 | Marek’s disease vaccines — an open-ended success story Immunization against Marek’s disease (MD) was started in the late 1960s and first used avirulent Marek’s disease virus (MDV) or a virus very closely related to MDV, turkey herpesvirus 1 (HVT), which does not cause disease. Vaccination reduced the incidence of MD by 99% and presents a unique example of the successful application of a modified-live virus (MLV) vaccine against an extremely aggressive agent that can routinely causes >90% morbidity and mortality in susceptible, unvaccinated hosts7,116. Because MDV strains are constantly evolving towards greater virulence in the face of vaccination109 (BOX 1), combination vaccines consisting of HVT and gallid herpesvirus type 3 or an attenuated MDV strain, CVI988-Rispens, are currently used117–119.

Clearly then, even a leaky vaccine can be used with great efficacy. What’s more is there is new research challenging the dogma of leaky vaccines selecting for greater virulence (emphasis mine):

We used controlled experiments involving natural virus transmission to reveal that vaccination with a leaky vaccine, which only marginally reduces transmission, can significantly reduce post-transmission disease development and mortality among unvaccinated contact individuals. Our analysis indicates that this effect is mediated by a reduction in exposure dose experienced by susceptible individuals when exposed to vaccinated shedders, leading to lower pathogen load and concomitant reduced symptoms in contact birds. The primary objectives of vaccination of livestock with leaky vaccines are to improve animal welfare and to reduce production losses caused by disease symptom development. Our results show that even partial vaccination against MD can substantially reduce disease symptoms and mortality in the whole flock, leading to universally positive impacts on animal welfare and productivity, and these conclusions may extend to leaky vaccines used in other systems.

Ending COVID-19 will require vaccination- this is not a matter of debate or discussion. Viruses evolve towards greater transmissibility, but they cannot evolve unless they have hosts. Fortunately, SARS-CoV-2 and other coronaviruses are unique in that they have a proofreading RNA-dependent RNA polymerase that slows mutation rates by a factor of about 20, which means they are slower to mutate, but this is irrelevant if they can infect well over 20 times more people than other RNA viruses. Vaccines clearly reduce viral load, prevent severe disease, and disrupt transmission, and they can thankfully be readily modified to address problematic variants as is done every season for influenza with great effect. They are the way out until someone proposes something better. Bossche doesn’t and his claims are baseless.

References

1. Correlates of vaccine-induced protection: methods and implications [Internet]. Who.int. [cited 2021 Mar 14];Available from: https://apps.who.int/iris/bitstream/handle/10665/84288/WHO_IVB_13.01_eng.pdf;sequence=1

2. Gandon S, Mackinnon MJ, Nee S, Read AF. Imperfect vaccines and the evolution of pathogen virulence. Nature 2001;414(6865):751–6.

3. Kupferschmidt K. INFECTIOUS DISEASES. Risk of “leaky” vaccines debated. Science 2015;349(6247):461–2.

4. Wagstaffe HR, Clutterbuck EA, Bockstal V, et al. Antibody-dependent natural killer cell activation after Ebola vaccination. J Infect Dis [Internet] 2019 [cited 2021 Mar 15];Available from: https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiz657/5672569

5. Long EO, Kim HS, Liu D, Peterson ME, Rajagopalan S. Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu Rev Immunol 2013;31:227–58.

6. Osterrieder N, Kamil JP, Schumacher D, Tischer BK, Trapp S. Marek’s disease virus: from miasma to model. Nat Rev Microbiol 2006;4(4):283–94.

7. Bailey RI, Cheng HH, Chase-Topping M, et al. Pathogen transmission from vaccinated hosts can cause dose-dependent reduction in virulence. PLoS Biol 2020;18(3):e3000619.

8. Tokars JI, Patel MM, Foppa IM, Reed C, Fry AM, Ferdinands JM. Waning of measured influenza vaccine effectiveness over time: the potential contribution of leaky vaccine effect. Clin Infect Dis 2020;71(10):e633–41.

9. Neuzil KM, Dupont WD, Wright PF, Edwards KM. Efficacy of inactivated and cold-adapted vaccines against influenza A infection, 1985 to 1990: the pediatric experience. Pediatr Infect Dis J 2001;20(8):733–40.

10. Quast I, Tarlinton D. B cell memory: understanding COVID-19. Immunity 2021;54(2):205–10.

11. Yezli S, Otter JA. Minimum infective dose of the major human respiratory and Enteric viruses transmitted through food and the environment. Food Environ Virol 2011;3(1):1–30.

12. Altmann DM, Boyton RJ, Beale R. Immunity to SARS-CoV-2 variants of concern. Science 2021;371(6534):1103–4.

13. Robson F, Khan KS, Le TK, et al. Coronavirus RNA proofreading: Molecular basis and therapeutic targeting. Mol Cell 2020;79(5):710–27.

14. Kemp SA, Collier DA, Datir RP, et al. SARS-CoV-2 evolution during treatment of chronic infection. Nature 2021;1–10.

15. Wei WE, Li Z, Chiew CJ, Yong SE, Toh MP, Lee VJ. Presymptomatic transmission of SARS-CoV-2 - Singapore, January 23-March 16, 2020. MMWR Morb Mortal Wkly Rep 2020;69(14):411–5.

16. Challen R, Brooks-Pollock E, Read JM, Dyson L, Tsaneva-Atanasova K, Danon L. Risk of mortality in patients infected with SARS-CoV-2 variant of concern 202012/1: matched cohort study. BMJ 2021;372:n579.

17. expert reaction to paper looking at mortality in patients infected with the SARS-CoV-2 variant of concern B.1.1.7 [Internet]. Sciencemediacentre.org. [cited 2021 Mar 15];Available from: https://www.sciencemediacentre.org/expert-reaction-to-paper-looking-at-mortality-in-patients-infected-with-the-sars-cov-2-variant-of-concern-b-1-1-7/

18. Sattler A, Angermair S, Stockmann H, et al. SARS-CoV-2-specific T cell responses and correlations with COVID-19 patient predisposition. J Clin Invest 2020;130(12):6477–89.

19. de Candia P, Prattichizzo F, Garavelli S, Matarese G. T cells: Warriors of SARS-CoV-2 infection. Trends Immunol 2021;42(1):18–30.

20. Ehrenstein MR, Notley CA. The importance of natural IgM: scavenger, protector and regulator. Nat Rev Immunol 2010;10(11):778–86.

21. Surveillance Manual | Mumps [Internet]. Cdc.gov. 2020 [cited 2021 Mar 15];Available from: https://www.cdc.gov/vaccines/pubs/surv-manual/chpt09-mumps.html

22. Surveillance Manual | Measles [Internet]. Cdc.gov. 2019 [cited 2021 Mar 15];Available from: https://www.cdc.gov/vaccines/pubs/surv-manual/chpt07-measles.html

23. Surveillance Manual | Meningococcal [Internet]. Cdc.gov. 2020 [cited 2021 Mar 15];Available from: https://www.cdc.gov/vaccines/pubs/surv-manual/chpt08-mening.html

24. Merler S, Ajelli M, Fumanelli L, et al. Containing Ebola at the source with ring vaccination. PLoS Negl Trop Dis 2016;10(11):e0005093.

25. Novavax confirms high levels of efficacy against original and variant COVID-19 strains in United Kingdom and South Africa trials [Internet]. Novavax.com. [cited 2021 Mar 15];Available from: https://ir.novavax.com/news-releases/news-release-details/novavax-confirms-high-levels-efficacy-against-original-and-0

26. Tarke A, Sidney J, Methot N, et al. Negligible impact of SARS-CoV-2 variants on CD4 + and CD8 + T cell reactivity in COVID-19 exposed donors and vaccinees. bioRxivorg [Internet] 2021;Available from: https://www.biorxiv.org/content/10.1101/2021.02.27.433180v1.full.pdf

27. Siegrist C-A. Vaccine Immunology [Internet]. Who.int. [cited 2021 Mar 15];Available from: https://www.who.int/immunization/documents/Elsevier_Vaccine_immunology.pdf

28. Derdeyn CA, Moore PL, Morris L. Development of broadly neutralizing antibodies from autologous neutralizing antibody responses in HIV infection [Internet]. Lww.com. [cited 2021 Mar 15];Available from: https://journals.lww.com/co-hivandaids/Abstract/2014/05000/Development_of_broadly_neutralizing_antibodies.3.aspx

29. Wang Z, Schmidt F, Weisblum Y, et al. mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants. Nature [Internet] 2021;Available from: https://www.nature.com/articles/s41586-021-03324-6.pdf

30. Laczkó D, Hogan MJ, Toulmin SA, et al. A single immunization with nucleoside-modified mRNA vaccines elicits strong cellular and humoral immune responses against SARS-CoV-2 in mice. Immunity 2020;53(4):724-732.e7.

31. Anderson EJ, Rouphael NG, Widge AT, et al. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. N Engl J Med 2020;383(25):2427–38.

32. Moyo-Gwete T, Madzivhandila M, Makhado Z, et al. SARS-CoV-2 501Y.V2 (B.1.351) elicits cross-reactive neutralizing antibodies. bioRxivorg [Internet] 2021;Available from: https://www.biorxiv.org/content/10.1101/2021.03.06.434193v2.full.pdf

33. Iannelli V. Who is Geert Vanden Bossche? [Internet]. Vaxopedia.org. 2021 [cited 2021 Mar 15];Available from: https://vaxopedia.org/2021/03/14/who-is-geert-vanden-bossche/?fbclid=IwAR3IjWL0v266FdeEt650U0F36vEH7EBRXdeiqlUyKyO2x-6XqlxMKDD5oCk

34. Murphy K, Weaver C. Janeway’s Immunobiology. 9th ed. Boca Raton, FL: CRC Press; 2016.

35. Carvalho T, Krammer F, Iwasaki A. The first 12 months of COVID-19: a timeline of immunological insights. Nat Rev Immunol [Internet] 2021;Available from: http://dx.doi.org/10.1038/s41577-021-00522-1

36. Paolini R, Bernardini G, Molfetta R, Santoni A. NK cells and interferons. Cytokine Growth Factor Rev 2015;26(2):113–20.

37. Maucourant C, Filipovic I, Ponzetta A, et al. Natural killer cell immunotypes related to COVID-19 disease severity. Sci Immunol 2020;5(50):eabd6832.

38. Temming AR, de Taeye SW, de Graaf EL, et al. Functional attributes of antibodies, effector cells, and target cells affecting NK cell-mediated antibody-dependent cellular cytotoxicity. J Immunol 2019;203(12):3126–35.

39. Bendelac A, Savage PB, Teyton L. The biology of NKT cells. Annu Rev Immunol 2007;25(1):297–336.

40. Choe PG, Kim K-H, Kang CK, et al. Antibody responses 8 months after asymptomatic or mild SARS-CoV-2 infection. Emerg Infect Dis 2021;27(3):928–31.

41. Netea MG, Domínguez-Andrés J, Barreiro LB, et al. Defining trained immunity and its role in health and disease. Nat Rev Immunol 2020;20(6):375–88.

42. CDC. What are the benefits of flu vaccination? [Internet]. Cdc.gov. 2021 [cited 2021 Mar 15];Available from: https://www.cdc.gov/flu/prevent/vaccine-benefits.htm

43. Arnaout R, Lee RA, Lee GR, et al. SARS-CoV2 testing: The limit of detection matters. bioRxivorg [Internet] 2020;Available from: http://dx.doi.org/10.1101/2020.06.02.131144

44. Voysey M, Costa Clemens SA, Madhi SA, et al. Single dose administration, and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine. SSRN Electron J [Internet] 2021 [cited 2021 Mar 15];Available from: https://papers.ssrn.com/abstract=3777268

45. Hall VJ, Foulkes S, Saei A, et al. Effectiveness of BNT162b2 mRNA vaccine against infection and COVID-19 vaccine coverage in healthcare workers in England, multicentre prospective cohort study (the SIREN study). SSRN Electron J [Internet] 2021 [cited 2021 Mar 15];Available from: https://papers.ssrn.com/abstract=3790399

46. JANSSEN BIOTECH, INC. (A PHARMACEUTICAL COMPANY OF JOHNSON & JOHNSON) COVID-19 Vaccine Ad26.COV2.S VAC31518 (JNJ-78436735) SPONSOR BRIEFING DOCUMENT ADDENDUM VACCINES AND RELATED BIOLOGICAL PRODUCTS ADVISORY COMMITTEE [Internet]. Fda.gov. [cited 2021 Mar 15];Available from: https://www.fda.gov/media/146218/download