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Profiteering from vaccine inequity: a crime against humanity?

BMJ 2021; 374 doi: (Published 16 August 2021) Cite this as: BMJ 2021;374:n2027

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Re: Profiteering from vaccine inequity: a crime against humanity?

Dear Editor,

I wholeheartedly agree with the argument well-presented by Hassan, Yamey and Abbasi.1 However, I see missing a key element which would make vaccine inequity – but also vaccine hesitancy – a more threatening issue than it already is. It centers on the issue of imperfect vaccine deployment and pathogen evolution.

Previously, epidemiology professors David Kennedy and Andrew Read sketched two reasons behind pathogens not evolving to resist vaccines as they do with drugs; one of which is that vaccines work early to prevent infection (prophylaxis) rather than later whence the pathogen is established within its host.2 However, once this attribute is compromised, there is an increased risk for the accumulation of the pathogen’s genetic diversity as to escape the effect of vaccination – best illustrated with the rise of Haemophilus influenzae infections in the Netherlands back in 2005.3

Covid-19 vaccines were initially targeted at reducing symptomatic infections.4 Still, SARS-CoV-2 variants of concern (VOCs) are ever more successful at diluting this effect, as seen with the higher frequency of infections by the Delta rather than the Alpha variant – more so in single dose than in full dose vaccinees.5 Indeed, it was recently estimated that 35,000 symptomatic breakthrough infections (BI) are recorded weekly in the US.6 Likewise in Israel, fully vaccinated individuals make up more than half of the newly reported infections but also more than half of severe or critical hospitalizations – keeping in mind that 78% of Israelis aged 12 and older are fully vaccinated.7 Therefore, vaccine-resistant variants are very much a reality by now.

Back to Kennedy and Read, an extreme differential in vaccine distribution as seen with SARS-CoV-2 allows in theory for the persistence of initially labeled ‘lethal’ variants in vaccinated populations. Simply put, certain variants of SARS-CoV-2 might be too virulent to propagate in immunologically naïve cohorts due to the severe complications they bring about to their hosts – most evidently due to death, but also less mobility and contact with other carriers. More healthy individuals, such as vaccinees, can nonetheless accommodate these variants to circulate without serious risk of infection. This comes at the grave price of a potential severe spillover onto the unvaccinated, willingly so or otherwise. While real-world evidence for this theory comes from non-human infections,8 9 it was recently modeled to be the case for the Covid-19 pandemic.10

There is also evidence for heightened genomic diversity in vaccine-resistant infections, as recently shown in a study from New York city. By comparing 76 BI sequences to 1,046 sequences of unvaccinated infections, authors report an enrichment of NTD deletions and RBD escape spike mutations in BI sequences, whereby mutation frequency was higher at the 47 BI-enriched sites (23 excluding unique mutations) compared to the 182 unvaccinated-enriched sites.11 This is reminiscent of the high rates of mutation accumulation seen with the emergence of the B.1.1.7/Alpha variant.12 As such, vaccines will not only allow the circulation of existing VOCs but can even facilitate the rise of new ones.

Some have optimistically argued that SARS-CoV-2 is expected to reach peak fitness at some point as to restrict the emergence of new variants13 and follow suit the endemic profiles of other coronaviruses.14 15 Moreover, considering SARS-CoV-2 evolutionary dynamics to date, the successive dominance of ever more transmissible variants – first with D614G, then Alpha and now Delta – suggests that a switch to more virulent lineages is unlikely, especially given the growing population immunity through vaccination or natural infection.16 However, these propositions are not warranted. For instance, SARS-CoV-2 is efficiently optimizing its access to ACE2 receptors that are present in both the upper and lower respiratory tracts; as such, transmissibility and virulence can be coincidently enhanced.17 Also, certain settings have already proved to raise the bar of peak fitness, such as in immunocompromised patients and farmed mink reservoirs.18 Vaccinated populations are therefore just the next battlefield in our arms race with SARS-CoV-2.

To put these concerns to rest, we need more and consistent genomic surveillance of BI variants - by the end of April, only 555 collected specimens (5%) were sequenced out of at least 10,000 BI cases in the US.19 In addition, unlike the study discussed above, the concern of most genomic studies addressing BI variants is limited to the representation of specific existing VOCs in vaccinees 20-23 but not how the added selection pressure caused by vaccines affects SARS-CoV-2 evolution.

With vaccine inequity and hesitancy, the damages can be almost instantly observed as shown by this article. But more threatening is the long-term aftermath of variants surviving the vaccine effect and going back to infect still-susceptible individuals globally but also domestically.

1. Hassan F, Yamey G, Abbasi K. Profiteering from vaccine inequity: a crime against humanity? BMJ 2021;374:n2027. doi: 10.1136/bmj.n2027 [published Online First: 2021/08/18]
2. Kennedy DA, Read AF. Why does drug resistance readily evolve but vaccine resistance does not? Proc Biol Sci 2017;284(1851) doi: 10.1098/rspb.2016.2562 [published Online First: 2017/03/31]
3. Schouls LM, van der Ende A, van de Pol I, et al. Increase in genetic diversity of Haemophilus influenzae serotype b (Hib) strains after introduction of Hib vaccination in The Netherlands. J Clin Microbiol 2005;43(6):2741-9. doi: 10.1128/JCM.43.6.2741-2749.2005 [published Online First: 2005/06/16]
4. Doshi P. Will covid-19 vaccines save lives? Current trials aren't designed to tell us. BMJ 2020;371:m4037. doi: 10.1136/bmj.m4037 [published Online First: 2020/10/23]
5. Lopez Bernal J, Andrews N, Gower C, et al. Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant. N Engl J Med 2021 doi: 10.1056/NEJMoa2108891 [published Online First: 2021/07/22]
6. Abutaleb Y, Johnson CY, Achenbach J. ‘The war has changed’: Internal CDC document urges new messaging, warns delta infections likely more severe. The Washington Post 2021. Last Accessed: 19 August 2021.
7. Wadman M. A grim warning from Israel: Vaccination blunts, but does not defeat Delta. Science 2021. Last Accessed: 19 August 2021.
8. Barclay VC, Sim D, Chan BH, et al. The evolutionary consequences of blood-stage vaccination on the rodent malaria Plasmodium chabaudi. PLoS Biol 2012;10(7):e1001368. doi: 10.1371/journal.pbio.1001368 [published Online First: 2012/08/08]
9. Read AF, Baigent SJ, Powers C, et al. Imperfect Vaccination Can Enhance the Transmission of Highly Virulent Pathogens. PLoS Biol 2015;13(7):e1002198. doi: 10.1371/journal.pbio.1002198 [published Online First: 2015/07/28]
10. Miller IF, Metcalf CJE. Assessing the risk of vaccine-driven virulence evolution in SARS-CoV-2. medRxiv 2021:2020.12.01.20241836. doi: 10.1101/2020.12.01.20241836
11. Duerr R, Dimartino D, Marier C, et al. Dominance of alpha and Iota variants in SARS-CoV-2 vaccine breakthrough infections in New York City. J Clin Invest 2021 doi: 10.1172/JCI152702 [published Online First: 2021/08/11]
12. Rambaut A, Loman N, Pybus O, et al. Preliminary genomic characterisation of an emergent SARS-CoV-2 lineage in the UK defined by a novel set of spike mutations. 2020. Last Accessed: 19 August 2021.
13. Burioni R, Topol EJ. Has SARS-CoV-2 reached peak fitness? Nat Med 2021 doi: 10.1038/s41591-021-01421-7 [published Online First: 2021/06/23]
14. Eguia RT, Crawford KHD, Stevens-Ayers T, et al. A human coronavirus evolves antigenically to escape antibody immunity. PLoS Pathog 2021;17(4):e1009453. doi: 10.1371/journal.ppat.1009453 [published Online First: 2021/04/09]
15. Vijgen L, Keyaerts E, Moes E, et al. Complete genomic sequence of human coronavirus OC43: molecular clock analysis suggests a relatively recent zoonotic coronavirus transmission event. J Virol 2005;79(3):1595-604. doi: 10.1128/JVI.79.3.1595-1604.2005 [published Online First: 2005/01/15]
16. van Dorp L, Houldcroft CJ, Richard D, et al. COVID-19, the first pandemic in the post-genomic era. Current Opinion in Virology 2021
17. Telenti A, Arvin A, Corey L, et al. After the pandemic: perspectives on the future trajectory of COVID-19. Nature 2021 doi: 10.1038/s41586-021-03792-w [published Online First: 2021/07/09]
18. Harvey WT, Carabelli AM, Jackson B, et al. SARS-CoV-2 variants, spike mutations and immune escape. Nat Rev Microbiol 2021;19(7):409-24. doi: 10.1038/s41579-021-00573-0 [published Online First: 2021/06/03]
19. COVID C, Team VBCI, COVID C, et al. COVID-19 Vaccine Breakthrough Infections Reported to CDC—United States, January 1–April 30, 2021. Morbidity and Mortality Weekly Report 2021;70(21):792.
20. Gupta N, Kaur H, Yadav P, et al. Clinical characterization and Genomic analysis of COVID-19 breakthrough infections during second wave in different states of India. medRxiv 2021:2021.07.13.21260273. doi: 10.1101/2021.07.13.21260273
21. Kustin T, Harel N, Finkel U, et al. Evidence for increased breakthrough rates of SARS-CoV-2 variants of concern in BNT162b2-mRNA-vaccinated individuals. Nat Med 2021 doi: 10.1038/s41591-021-01413-7 [published Online First: 2021/06/16]
22. McEwen AE, Cohen S, Bryson-Cahn C, et al. Variants of concern are overrepresented among post-vaccination breakthrough infections of SARS-CoV-2 in Washington State. Clin Infect Dis 2021 doi: 10.1093/cid/ciab581 [published Online First: 2021/06/25]
23. Olsen RJ, Christensen PA, Long SW, et al. Trajectory of Growth of SARS-CoV-2 Variants in Houston, Texas, January through May 2021 Based on 12,476 Genome Sequences. Am J Pathol 2021 doi: 10.1016/j.ajpath.2021.07.002 [published Online First: 2021/07/26]

Competing interests: No competing interests

19 August 2021
Saad O. Omais
PhD candidate in Cellular and Molecular Biology
American University of Beirut
Beirut, Lebanon