What can we expect from first-generation COVID-19 vaccines?

A first generation of COVID-19 vaccines is expected to gain approval as soon as the end of 2020 or early 2021. A popular assumption is that these vaccines will provide population immunity that can reduce transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and lead to a resumption of pre-COVID-19 “normalcy”. Given an initial reproduction number of around 2·2,¹ which has since been revised to as high as about 4, and taking into account overdispersion of infections,² perhaps about 25–50% of the population would have to be immune to the virus to achieve suppression of community transmission.1, 2, 3

Multiple COVID-19 vaccines are currently in phase 3 trials with efficacy assessed as prevention of virologically confirmed disease.⁴ WHO recommends that successful vaccines should show disease risk reduction of at least 50%, with 95% CI that true vaccine efficacy exceeds 30%.⁵ However, the impact of these COVID-19 vaccines on infection and thus transmission is not being assessed. Even if vaccines were able to confer protection from disease, they might not reduce transmission similarly.

Challenge studies in vaccinated primates showed reductions in pathology, symptoms, and viral load in the lower respiratory tract,6, 7 but failed to elicit sterilising immunity in the upper airways. Sterilising immunity in the upper airways has been claimed for one vaccine, but peer-reviewed publication of these data are awaited.⁸ There have been reports of virologically confirmed SARS-CoV-2 re-infection of previously infected individuals, but the extent of such re-infection is unclear.⁹ Whether re-infection is associated with secondary spread is unknown.

The immunological correlates of protection from SARS-CoV-2 infection and COVID-19 have yet to be elucidated. Pre-existing neutralising antibody seemed to have afforded protection against re-infection in people on board a fishing vessel where there was an outbreak of SARS-CoV-2 with a high infection attack rate.¹⁰ In animal models, passive antibody transfer protected against COVID-19,11, 12 whereas neutralising antibody correlated with protection after inoculation.¹³ However, the roles of mucosal immunity, other biological antibody activities (eg, antibody-dependent cellular cytotoxicity), and T cells in protection conferred by natural infection or passive immunisation are unclear.

The prevalence and duration of neutralising antibody responses after natural infection remain to be defined by gold-standard neutralisation assays that use live virus rather than pseudotype neutralising assays or non-functional ELISA assays.¹⁴ The duration of protection against re-infection with seasonal human coronaviruses might last for less than a year.¹⁵ Middle East respiratory syndrome coronavirus (MERS-CoV) re-infection occurs in dromedary camels, the natural host of that virus.¹⁶ Whether re-infected camels are as infectious as those with primary infections is not known. The observation that MERS-CoV is enzootic in dromedary populations despite high (>90%) seroprevalence in juvenile and adult camels implies that virus transmission may not be functionally interrupted by previous infection. Also relevant is how influenza vaccines can reduce disease transmission,¹⁷ whereas inactivated polio vaccines are effective at protecting from disease but have less effect on reduction of faecal shedding of poliomyelitis virus¹⁸ and thus possibly on transmission.

These observations suggest that we cannot assume COVID-19 vaccines, even if shown to be effective in reducing severity of disease, will reduce virus transmission to a comparable degree. The notion that COVID-19-vaccine-induced population immunity will allow a return to pre-COVID-19 “normalcy” might be based on illusory assumptions.

Another important consideration is COVID-19 vaccine allocation strategy. First principles would preferentially allocate vaccine supplies to people at high risk of severe morbidity and mortality. Preliminary model-informed analyses support this theoretical inference.¹⁹ However, vaccine allocation perspectives in addition to utilitarian considerations are important. The US National Academy of Medicine's Preliminary Framework for Equitable Allocation of COVID-19 Vaccines identified other foundational criteria, such as equal regard, mitigation of health inequities, fairness, and transparency, that should also determine vaccine allocation.²⁰ Alongside the risks of severe morbidity and mortality and of disease transmission, this framework stipulates two additional criteria for equitable vaccine allocation—namely, risks of acquiring infection and of negative societal impact.²⁰ Front-line health-care and essential workers, such as school teachers, belong in both these latter groups.

Policy makers must be vigilant of the possible impact of vaccine hesitancy.²¹ In the COVID-19 response, the activities of some politicians have been incompatible with science and risk further eroding vaccine confidence among the general public. The potential disruption of a proportion of people declining vaccine uptake could be substantial. The likely heterogeneity of such abreactions to vaccination roll-outs between countries and across partisan divides within nations should not be underestimated. Finally, if international travel were to fully recommence, vaccine allocation to different countries with varying means of access will require careful deliberation, based on moral grounds and because no country will be truly protected from COVID-19 until virtually the entire world is.²²

Notwithstanding these caveats, COVID-19 vaccines are needed, even if they have minimal impact on transmission and despite the challenges of vaccine allocation. What such vaccines are likely to achieve might not be herd immunity. If so, strategies for how we use such vaccines would have to be based on other considerations. Will vaccines that protect healthy young adults also protect groups vulnerable to severe disease such as older adults and those with comorbidities? Influenza vaccines are less effective in older populations than in younger populations, partly due to immune senescence,²³ which might similarly affect COVID-19 vaccines. However, the so-called original antigenic sin in influenza vaccines that arises from sequential infections by or vaccinations with antigenically closely related strains²⁴ is not relevant to coronaviruses. If COVID-19 vaccines have acceptable effectiveness in reducing morbidity and mortality in high-risk groups, they would have an important role, irrespective of impact on transmission and population immunity. If high-risk populations can be shielded by vaccination, COVID-19 control measures could be recalibrated. Crucially, it will be important to communicate to policy makers and the general public that first-generation vaccines are only one tool in the overall public health response to COVID-19 and unlikely to be the ultimate solution that many expect.

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