key: cord-0771539-fwjggimb
authors: Omrani, Ali S.; Tleyjeh, Imad M.
title: Which are the best COVID-19 vaccines?
date: 2021-08-21
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2021.08.012
sha: df4d72b7d4489ab2c18438ce2db8c479b678c48d
doc_id: 771539
cord_uid: fwjggimb

nan

and CoronaVac (Sinovac), and the adjuvanted NVX-CoV2373 (Novavax) vaccine. [1] In their respective registrational, randomised clinical trials (RCTs), these vaccines were shown to have a range of efficacies using similar, but not identical endpoints (Table 1) 

RCTs had considerably different trial protocols, endpoint definitions, triggers for real-time polymerase chain reaction (RT-PCR) testing, ascertainment procedures, and follow up durations. [1, 2] Moreover, the backdrop to the different RCTs differed widely in terms of risk of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and transmission dynamics, circulating SARS-CoV-2 variants of concern, and adherence to nonpharmacological control interventions. [1] [2] [3] COVID-19 vaccines are often compared based on their reported efficacy results. However, without careful consideration and textualization, such direct comparisons can be misleading. While randomisation may ensure comparability of groups within individual trials, it does not permit comparisons between trials. The potential incomparability of COVID-19 vaccine trial results was not unforeseen. In their blueprint for the development of COVID-19 vaccines, the World Health Organization recommended an adaptive trial design with multiple candidates being evaluated in parallel against a single placebo and under a common protocol. [3] Importantly, stringent regulatory oversight and transparent trial J o u r n a l P r e -p r o o f reporting are crucial elements for the informed assessment of benefits and risks associated with COVID-19 vaccines. Unfortunately, such elements have not always been forthcoming. [4] By definition, vaccine RCTs are executed under idealised conditions to enable robust evaluations and support regulatory marketing authorisation. Vaccine efficacy represents the relative risk reduction achieved in vaccinated versus unvaccinated populations in RCT settings. Once deployed in a wider population, vaccine effectiveness describes the relative risk reduction attributable to the vaccine in real-world settings. Vaccine efficacy does not necessarily predict vaccine effectiveness in specific settings. [3] For example, vaccine effectiveness achieved with BNT162b2 (Pfizer-BioNTech) or ChAdOx1 (AstraZeneca-Oxford) vaccines in national rollouts matched or exceeded the efficacies reported in their respective randomised trials. [1, 5] On the other hand, BBIBP-CorV (Beijing Institute-Sinopharm) and WIBP-CorV (Wuhan Institute-Sinopharm) were associated with efficacies of 64 to 78.1% in their phase III RCT, but their effectiveness in the real-world appear to be considerably below such rates. [1, 6] The ultimate aim of COVID-19 vaccines is to mitigate severe health outcomes, including death, and to reduce its impact on healthcare services. However, adequately powered RCTs to evaluate severe COVID-19 are not feasible, especially amongst younger age groups and in those without co-existing medical co-morbidities. [3] Furthermore, the interpretation of vaccine effect on disease severity may be confounded by differences in risk mitigation practices amongst high-risk populations, as well as variable access to high quality medical care and to therapeutics that may reduce the risk of disease progression (e.g.; monoclonal antibodies) or mortality (e.g.; systemic corticosteroids, tocilizumab), and the locally circulating SARS-CoV-2 variants. Although severe COVID-19 outcomes are often evaluated in J o u r n a l P r e -p r o o f RCTs as secondary outcomes, the comparisons across different vaccines remain subject to the same trial-to-trial incomparability discussed above. On the other hand, useful differential clinical effectiveness may be observed in some real-world vaccine effectiveness studies. [5, 7] However, the non-randomised nature of these studies may limit their internal validity.

Another important aim of COVID-19 vaccines is to prevent or reduce asymptomatic SARS- Beyond vaccine efficacy, safety is an important differential consideration. Rigorous postmarketing surveillance is essential to identify rare adverse events that may not be detected in registrational RCTs. Post-vaccination thrombosis with thrombocytopenia syndrome (TTS), characterised by acute arterial or venous thrombotic events with low platelet count and J o u r n a l P r e -p r o o f detectable platelet factor-4-heparin antibodies, was reported in association with ChAdOx1 (AstraZeneca-Oxford) and Ad26.COV2.S (Janssen) vaccines. [9] The estimated incidence of TTS is one to ten and one to seven per one million in ChAdOx1 (AstraZeneca-Oxford) and

Ad26.COV2.S (Janssen) recipients, respectively. [10, 11] After meticulous risk-benefit assessments, the European Medicines Agency (EMA) concluded that the risk of severe COVID-19 outcomes outweighs the rare risk of ChAdOx1 (AstraZeneca-Oxford)-associated TTS. [10] Similarly, the United States' Advisory Committee on Immunization Practices (ACIP) advised that the benefits of Ad26.COV2.S (Janssen) outweigh the exceedingly small risk of TTS. [11] Neither EMA nor ACIP consider ChAdOx1 (AstraZeneca-Oxford) or Ad26.COV2.S (Janssen) contraindicated for any sex or age group. [10, 11] There have also been rare reports of myocarditis and pericarditis in association with BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna). [12] However, the relatedness of myocarditis and pericarditis to COVID-19 vaccines has not been confirmed.

It is noteworthy that of the 21 COVID-19 vaccines in current use, potentially serious adverse events have thus far only been identified in association with COVID-19 vaccines that are authorised in countries with robust pharmacovigilance procedures and regulatory monitoring. [10, 12] Though intended to evaluate, quantify and contextualise any potential vaccine-related adverse events, the reporting of serious adverse events potentially linked to COVID-19 vaccines resulted in negative publicity and inconsistent public health messaging.

In turn, this contributed to lower public acceptance of certain COVID-19 vaccine brands, while elevating others. Perhaps unwittingly, some ended up preferring COVID-19 vaccines with no publicly available post-marketing effectiveness or safety data over those with comprehensive and carefully calibrated benefit-risk assessments. [13] To make informed vaccines experienced periods of short supply and delayed deliveries. [19] In the case of Sputnik V (Gamaleya), which consists of an adenovirus 26-verctored first dose and an adenovirus 5-vectored second dose, delays in the delivery of the second dose forced some national programs to cancel their orders or to use alternative vaccines as second doses. [20] Heterologous ChAdOx1 nCoV-19 and mRNA vaccines was shown to result in potent induction of SARS-CoV-2 S-specific antibodies. [21] However, there are no peer-reviewed clinical data to guide heterologous COVID-19 vaccination.

Last, but not least, COVID-19 vaccine procurement costs and logistic requirements have obvious implications for policy makers (Table 1) (Table 1) . Moreover, a single-dose schedule, such as that of Ad26.COV2.S (Janssen), may be appealing in settings where resources cannot accommodate two-dose vaccine schedules. Decision makers will need to balance vaccine efficacy and safety data against the available resources. These can be complex considerations and may lead to pragmatic decisions driven by accessibility, feasibility, and prioritisation. In some settings, a moderately efficacious but affordable vaccine with relatively simple logistics may yield superior public health benefits compared with highly efficacious but unfeasible alternatives. Realistically, the ablility to choose certain J o u r n a l P r e -p r o o f COVID-19 vaccines over others is a privilege that is not enjoyed by a majority of the human population. Based on predicted 12-week mortality modelling, Latin America, central and eastern Europe, central Asia and southern Africa are the regions with the highest COVID-19 vaccine needs to avert the worst clinical outcomes. [23] The same are regions where COVID-19 vaccine coverage has so far been disappointingly low. [1] In conclusion, rather than by direct comparison of vaccine efficacy data, differentiation of the available COVID-19 vaccines requires careful evaluation of the available evidence in its totality. Based on the completeness and accessibility of the data derived from phase III clinical trials, the breadth and depth of real-world data on safety and effectiveness, including against SARS-CoV-2 variants, and the complexity of the required logistics for mass deployment, we consider BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) the preferred COVID-19 vaccines where the required economic and organisational means are available. Otherwise, ChAdOx1 (AstraZeneca-Oxford) and Ad26.COV2.S (Janssen) could be reasonable alternatives. The remaining COVID-19 vaccines in current use have considerable gaps in their peer-reviewed published evidence base, including limited or absent corroboration from real-world data to elucidate their effectiveness or safety.

ASO has received speaker honoraria and advisory board participation fees from Pfizer, Merck, and Gilead, all unrelated to this manuscript. IMT has no conflict of interest in relation to this manuscript.

No funding was required.

J o u r n a l P r e -p r o o f 

The London School of Hygiene and Tropical Medicine Vaccine Centre, COVID-19 vaccine tracker

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AstraZeneca's COVID-19 vaccine: benefits and risks in context

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Vaccine brand "comparison shopping" presents a critical public health challenge

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ASO prepared the manuscript. IMT