Vaccine Nationalism Will Ensure That SARS-CoV-2 Wins

As a species, we are bad at sharing. We proved it in 2009 with the H1N1 pandemic, and then we proved it again with COVID-19. Many global health experts feel that the messaging in attempting to secure access to vaccines for nations where they would otherwise be inaccessible should emphasize solidarity against the global threat of the virus. Morally, I am in absolute agreement. I think Dr. Hassoun makes an excellent case for this point which she writes in response to the analysis put forth by Ferguson and Caplan:

Canada, for instance, has already secured enough to vaccinate its entire population nine times over, and the USA, European Union, UK, Australia and Japan can vaccinate their populations between 2 and 8x 1.

…

No one deserves the luck of their birth and few have much control over their country of residence. So, when there are four ventilators per 12 million people in some low-income and middle-income countries, and people are being buried in cardboard boxes in mass graves, it is simply unconscionable to argue that wealthy countries can keep their vaccines to themselves or even help their populations first.

In essence, Hassoun is arguing against vaccine nationalism, which is defined by Bollyky and Brown:

Absent an international, enforceable commitment to distribute vaccines globally in an equitable and rational way, leaders will instead prioritize taking care of their own populations over slowing the spread of COVID-19 elsewhere or helping protect essential health-care workers and highly vulnerable populations in other countries.

The humanitarian case against vaccine nationalism is self-evident and it is morally incumbent upon nations with the means to help to act, especially given the catastrophes in areas like India (which I will focus on here because I think it’s salient in everyone’s mind right now and because the devastation is difficult to even contemplate). But I know that for many people, the abstract idea of someone (or many someones) dying or becoming disabled somewhere (or many somewheres) else in the world from something that we have the capability to prevent is not enough to compel action- rather some level of self-interest is required. I wish that such motivations were secondary to the ethics of the situation, but alas, I’m going to make a case here that there is a very strong basis for wanting equitable vaccine distribution as a means towards self-serving ends for people who live in those nations which managed to secure a vaccine glut. A one-health approach is not just some cutesy theory- it may prove essential to our survival.

The fundamental reality of SARS-CoV-2, and all viruses, is that evolution is a certainty- it’s just a question of how fast. Each time SARS-CoV-2 copies its genome, it makes errors, even with the correction of its exonuclease (essentially a backspace button for when it’s copying things- sources vary in the extent to which it reduces the error rate but the reported range appears to be 15 to 1000 times). Each error is a point mutation- which can have any of a few outcomes:

Abdool Karim SS, de Oliveira T. New SARS-CoV-2 variants - clinical, public health, and vaccine implications. N Engl J Med [Internet]. 2021;(NEJMc2100362). Available from: http://dx.doi.org/10.1056/NEJMc2100362

1. “Nothing” changes. The genetic code is written in a manner that minimizes the impact of errors (e.g. the wobble effect) so this is the most common outcome.

   1. Even though nothing in the protein may change, it doesn’t necessarily mean that nothing has changed in the biology of the virus; cells have biases for certain codons (the 3 adjacent nucleotide sequences that specify a particular amino acid within a protein) and so changing them can affect the rate of replication, which is the basis for some concepts of live attenuated viral vaccines- deoptimize the codons to drastically slow the rate of replication and thus render the virus to be incapable of causing disease even though, formally, it looks just like the virus that does cause disease. The secondary structure of the RNA in the virus may also change from these mutations which can affect their biology.

2. The mutation is harmful for the virus and is selected against, meaning those specific viral particles are not good at spreading to other cells and replicating.

3. The mutation has a benefit to the virus and helps it to spread to more hosts.

This, however, is not the only way that SARS-CoV-2 can evolve. For one thing, in addition to point mutations, there can be indels (short for insertion/deletions). Additionally, coronaviruses can undergo recombination- their RNA-dependent RNA polymerase (RdRP) can begin replicating with one RNA strand, and then change to another one (discussed here). In other words, there are still many moves in the evolutionary landscape for SARS-CoV-2 to take. It’s also important to bear in mind that even though there are certain mutations and amino acid changes that concern us (e.g. spike E484K), these mutations can also interact with other mutations (epistasis) and thus the combination of certain mutations may have unexpected effects. This makes prediction of how any given change in the spike protein will affect vaccine efficacy a significant challenge. Additionally, while we are most concerned with mutations in spike as far as the protection from vaccines, SARS-CoV-2 has many other proteins which affect its host-pathogen interactions. South African virologist Penny Moore notes (regarding the apparent cross-reactive nature of antibodies against B.1.351, the variant from South Africa):

“I have infinite faith in the ability of a virus to escape an immune response,” she says. “We've got to lower the global number of infections to the point where the virus doesn’t have as many opportunities to escape.”

The reality of unmitigated spread of SARS-CoV-2 as happens in the absence of vaccination and non-pharmaceutical interventions (but we know how much people famously love those) is uncontrolled mutation and the emergence of variants. It does not matter that SARS-CoV-2 is slower to mutate than other RNA viruses if it has thousands of times more infectious cycles. Right now, for the most part, our vaccines seem to be holding up fairly well against variants depending on the specific vaccine- but without a well-defined correlate of protection to go with the vaccines it’s hard to judge exactly how well without rigorous clinical trials which take time (though there’s progress here too, but still, nothing definitive). But if as research is hinting towards, the mechanistic correlate of protection is neutralizing antibodies directed against spike, that could be a problem- spike is the most mutable part of SARS-CoV-2 because it faces the strongest selection pressures to evolve to escape immunity, and while we can hope that the evolutionary constraints on spike are stringent enough that the bounds of its evolution are well-confined, we have no guarantees here. As COVAX says: With a fast-moving pandemic, no one is safe, unless everyone is safe. It sounds cliché, almost Hallmark card-worthy, but it is completely true. COVID-19 started as far as we can tell in China, possibly from a wet market but some cases cannot be traced to one and likely with an intermediate host that is yet to be identified, and now there isn’t a part of the world it hasn’t touched.

Can you for a moment contemplate how horrific it would be to have all this progress made in combatting COVID-19 to the point that it is domestically basically nonexistent, only to have a new variant emerge that escapes previously-held immunity and set us back to square one? Consider what happened in Manaus- COVID-19 devastated the area to such an extent that it was thought that disease-acquired immunity reached levels needed for herd effects to kick in. And then after a break, hospitalizations soared. Why? Probably the emergence of a variant. SARS-CoV-2 keeps winning the genetic lottery and we have the power to make it stop buying tickets through aggressive vaccination and non-pharmaceutical interventions. Every single death from COVID-19 is now vaccine-preventable and the fact that people are still dying of it is an unacceptable tragedy. We have yet to see the emergence of a variant of high consequence- but in all likelihood, by the time we notice it, it will be too late for many people. Vaccination will slow the spread of this virus, prevent it from accumulating mutations that facilitate escape from the immune system, and it will save lives. Letting this virus ravage poorer parts of the world by way of our own complacency is a self-destructive act on top of being morally unconscionable. I implore everyone: the time to act is not now- it was months ago. We have to make up for lost time.

There is another piece to this selfish argument that also cannot be ignored. India is one of the world’s most important producers of vaccines. Globally, we are dependent on its manufacturing capacity to protect us- the Serum Institute of India manufactures 60% of the entire world’s vaccines. India cannot be an effective manufacturer if it is overwhelmed with COVID-19. And if other countries cannot vaccinate, SARS-CoV-2 plays the genetic lottery again, and per the law of large numbers, eventually it may win. It’s worse than that because India sits in a critical pharmaceutical supply chain and manufactures 18% of the raw material used for pharmaceuticals. COVID-19, as we have all come to realize, is not merely an infectious disease but rather a pestilence that manages to disrupt all parts of life.

No one is safe until everyone is safe. It is not enough to have vaccines. Vaccines do not save lives- vaccination does. A vaccine that isn’t available, or can’t be stored long enough to be used, or isn’t taken does not affect infectious diseases.

Please consider donating to these GoFundMe’s to help India. Please place pressure on your political officials to enhance efforts to support resource-poor nations devastated by COVID because we all depend on it.

References

1. Fidler DP. Vaccine nationalism’s politics. Science. 2020;369(6505):749.

2. Hassoun N. Against vaccine nationalism. J Med Ethics. 2021;medethics-2020-107193.

3. Mullard A. How COVID vaccines are being divvied up around the world. Nature [Internet]. 2020 [cited 2021 Mar 25]; Available from: https://www.nature.com/articles/d41586-020-03370-6

4. Advancing a “one health” approach to promote health at the human-animal-environment interface [Internet]. Apha.org. [cited 2021 Apr 5]. Available from: https://www.apha.org/policies-and-advocacy/public-health-policy-statements/policy-database/2018/01/18/advancing-a-one-health-approach

5. Plante JA, Mitchell BM, Plante KS, Debbink K, Weaver SC, Menachery VD. The variant gambit: COVID-19’s next move. Cell Host Microbe. 2021;29(4):508–15.

6. Flint SJ, Enquist LW, Racaniello VR, Rall GF, Skalka AM. Principles of Virology: 2 Vol set - Bundle. 4th ed. Washington, D.C., DC: American Society for Microbiology; 2015.

7. Callaway E. Rare COVID reactions might hold key to variant-proof vaccines. Nature. 2021;592(7852):20–1.

8. Abdool Karim SS, de Oliveira T. New SARS-CoV-2 variants - clinical, public health, and vaccine implications. N Engl J Med [Internet]. 2021;(NEJMc2100362). Available from: http://dx.doi.org/10.1056/NEJMc2100362

9. Le Nouën C, Collins PL, Buchholz UJ. Attenuation of human respiratory viruses by synonymous genome recoding. Front Immunol. 2019;10:1250.

10. Koonin EV, Novozhilov AS. Origin and evolution of the universal genetic code. Annu Rev Genet. 2017;51(1):45–62.

11. Smyth RP, Negroni M, Lever AM, Mak J, Kenyon JC. RNA structure-A neglected puppet master for the evolution of virus and host immunity. Front Immunol. 2018;9:2097.

12. Corbett KS, Nason MC, Flach B, Gagne M, O’ Connell S, Johnston TS, et al. Immune correlates of protection by mRNA-1273 immunization against SARS-CoV-2 infection in nonhuman primates. bioRxivorg [Internet]. 2021; Available from: https://www.biorxiv.org/content/10.1101/2021.04.20.440647v2.full.pdf

13. Chrisman BS, Paskov K, Stockham N, Tabatabaei K, Jung J-Y, Washington P, et al. Indels in SARS-CoV-2 occur at template-switching hotspots. BioData Min. 2021;14(1):20.

14. Kupferschmidt K. New coronavirus variants could cause more reinfections, require updated vaccines. Science [Internet]. 2021 [cited 2021 Apr 30]; Available from: https://www.sciencemag.org/news/2021/01/new-coronavirus-variants-could-cause-more-reinfections-require-updated-vaccines

15. (hq) WH. WHO-convened global study of origins of SARS-CoV-2: China Part [Internet]. Who.int. World Health Organization; 2021 [cited 2021 Apr 30]. Available from: https://www.who.int/publications/i/item/who-convened-global-study-of-origins-of-sars-cov-2-china-part

16. Cobey S, Larremore DB, Grad YH, Lipsitch M. Concerns about SARS-CoV-2 evolution should not hold back efforts to expand vaccination. Nat Rev Immunol. 2021;21(5):330–5.

17. CDC. Cases, Data, and Surveillance [Internet]. Cdc.gov. 2021 [cited 2021 Apr 30]. Available from: https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/variant-info.html

18. The New York Times. What to know about India’s Coronavirus crisis. The New York times [Internet]. 2021 Apr 30 [cited 2021 Apr 30]; Available from: https://www.nytimes.com/article/india-coronavirus-cases-deaths.html

19. Santhanam L. COVID-19 is out of control in India, where most vaccines are made. How did that happen? [Internet]. Pbs.org. 2021 [cited 2021 Apr 30]. Available from: https://www.pbs.org/newshour/health/covid-19-is-out-of-control-in-india-where-most-vaccines-are-made-how-did-that-happen

20. Mullin R. COVID-19 is reshaping the pharmaceutical supply chain [Internet]. Acs.org. [cited 2021 Apr 30]. Available from: https://cen.acs.org/business/outsourcing/COVID-19-reshaping-pharmaceutical-supply/98/i16

21. Gettleman J, Yasir S, Kumar H, Raj S, Loke A. As covid-19 devastates India, deaths go undercounted. The New York times [Internet]. 2021 Apr 24 [cited 2021 Apr 30]; Available from: https://www.nytimes.com/2021/04/24/world/asia/india-coronavirus-deaths.html