Further implications on the global real-world vaccine effectiveness against SARS-CoV-2

KEYWORDS:

• COVID-19
• vaccine effectiveness
• 4th dose
• booster
• Southeast Asia
• AZD1222
• BNT162b2
• Thailand

Dear Editor,

We have recently reported a global review of vaccine effectiveness (VE) data evaluating almost 80 real-world studies [1]. At the time of data extraction (10 February 2022), the vast majority of studies were limited to two-dose primary vaccination schedules and were predominantly conducted before the emergence of the Omicron variants. To address gaps in the data relating to VE against the Omicron variant, and significantly after the use of booster doses, we have already begun to evaluate a more recent data cut and hope to be able to share that analysis soon.

As we eagerly await updates to address data gaps relating to new schedules, we have noted a recent critical analysis from researchers at Chiang Mai University (CMU) in Thailand [2]. Like many countries worldwide, Thailand needed to adapt their vaccination schedules over time, proactively adopting heterologous vaccination schedules to manage vaccine availability issues. That happened so rapidly that there was little or no efficacy or effectiveness data to support decision-making. Randomized controlled trials almost exclusively assessed homologous schedules [3–5], and only recently has VE data become available for heterologous booster schedules [6–8]. Utilizing a unique active surveillance network established in Chiang Mai, Northern Thailand [9], the CMU team conducted a test-negative case–control study to assess the vaccine effectiveness of heterologous third (ChAdOx1 and BNT162b2) and fourth (ChAdOx1, BNT162b2 and mRNA-1273) dose schedules against SARS-CoV-2 infection during delta-predominant and omicron-predominant periods [2]. Over 95% of priming schedules in the study used either inactivated vaccines (Coronavac, Sinopharm) or ChAdOx1, or a combination of those three.

Consistent with previous studies [8], the CMU team noted a very high effectiveness against Delta infection (adjusted VE 97%, 95% CI 94–99%) with only moderate protection against Omicron infection (adjusted VE 31%, 95% CI 26–36%) after a third dose [2]. Importantly, they observed excellent protection against Omicron infection after a fourth dose (adjusted VE 75%, 95% CI 71–80%), and the observed VE was consistent across age groups for both delta and omicron infection. Similar to what was observed for the two dose schedules during our global review [1], the VE of third or fourth vaccine doses against omicron infection were comparable for the three main vaccines used for boosting in Thailand (viral vector and mRNA) [2]. Although the CMU study did not have sufficient events to compare VE of the third dose against delta by vaccine type, an earlier study by researchers in Bangkok found comparable protection from a third dose of viral vector and mRNA vaccines [8]. The protection offered by third or fourth doses in the CMU study was more evident against serious COVID-19 outcomes with observed VE being above 90–95% and suggests the current vaccines are providing very high levels of consistent protection over the first couple of months against the entire range of variants of concern (VOC) [2]. There are no widely established correlates of protection to predict VE with poorly predictive associations between neutralization data and observations of VE against severe COVID-19 outomes in the real world [10].

This is a critical observation for two reasons. First, we have seen rapid VOC evolution over the course of this pandemic, and this has driven continued discussions related to the development of variant-specific vaccines. At face value, this may seem like a much-needed continuous optimization approach to improving protection. However, it is crucial to consider the time and resources that go into developing new variant-specific vaccines, conducting registration trials to make them available, and public education to explain why new vaccines are necessary, in addition to the logistics required to change distribution networks to move from one vaccine to the next. At a practical level, confidence that the current vaccines may provide consistent protection against severe outcomes, irrespective of VOC enables governments to make longer-term strategic decisions regarding the future of their programs.

Secondly, because we have seen consistently high VE against serious outcomes despite these seemingly low neutralization titers, highlighting the importance of robust vaccine- or infection-induced cellular immunity against Omicron, the type of vaccine platform appears to be less critical. For example, our analysis noted equivalent VE for two-dose mRNA and viral vector vaccine schedules against serious outcomes due to VOCs before Omicron, despite the large differences in neutralization titers between different vaccine platforms [1]. With the new data from Thailand now reporting similar observations for third and fourth doses for both vaccine types against Omicron, we can have greater confidence that the choice of vaccine is far less critical than prioritizing high population coverage with a sufficient number of doses.

Importantly, the new data also suggest heterologous boosting schedules have the potential to provide very high levels of protection across a diverse range of variants, including Omicron. Homologous fourth dose VE data from Israel against the Omcron variant has been reported to be as low as 11–30% against SARS-CoV-2 infection and only slightly higher for the prevention of symptomatic disease (31–43%) [11]. Increasingly, discussions around the potential impact of original antigenic sin in the context of COVID-19 booster shots may require a reevaluation of homologous versus heterologous booster schedules to optimize protection.

Together, the essential new data demonstrate that prioritizing vaccination coverage must remain the key factor driving vaccine uptake. It is now clear that none of the available COVID-19 vaccines provides robust, lasting protection against infection, particularly in the Omicron era and likely due to inadequate and/or short-lived mucosal immunity. However, booster doses of all widely used vaccines offer very high levels of protection against severe outcomes. With this consistency of protection against severe disease across different variants, the case for developing variant-specific vaccines becomes less urgent, particularly if heterologous schedules can potentially circumvent some of the challenges homologous schedules may encounter in the face of new variants.

Declaration of interest

R Solante discloses consulting fees from AstraZeneca. C Alvarez-Moreno discloses grants from WHO solidarity COVID-19 vaccine studies, and speaker from GSK, Pfizer, Astra Zeneca. E Burhan, KP Hwang, A Macia, CH Nghia, JO Ibarra, HI Satari, A Rodriguez-Morales and S Chariyalertsak disclose consulting fees from AstraZeneca. NC Chiu discloses consulting fees from AstraZeneca and honoraria for scientific meeting travel and lecture from multiple companies. He is also a member of the Taiwan Vaccine Injury Compensation Program and Pediatric Infectious Disease Society of Taiwan. DV Dung discloses consulting fees and honoraria for advisory board attendance by AstraZeneca. S Kiertiburanakul discloses consulting fees from AstraZeneca and honoraria for lectures from AstraZeneca, Pfizer and Zuellig Pharma. PI Lee discloses grants from the Taiwan Center for Disease Control for COVID-19 vaccine immunogenicity studies, consulting fees from AstraZeneca, Merck Sharp & Dohme (MSD), and GlaxoSmithKline and payment for lectures from MSD. He also serves as the Chair, Advisory Committee on Immunization Practice in Taiwan. RC Lobo discloses consulting fees from AstraZeneca and honoraria for lectures from Menarini Philippines, Nestle, Mead Johnson and Novartis. He is also the vice-chair of the National Adverse Events Following Immunization committee in the Philippines. A Ong-Lim discloses honoraria for lectures from Moderna and is a member of the Technical Advisory Group, Department of Health in the Philippines. R Richtmann discloses consulting fees from AstraZeneca and honoraria for lectures from Pfizer and J&J. MAP Safadi discloses research grants and consultancy fees from Pfizer, GlaxoSmithKline, MSD, AstraZeneca, Janssen, and Sanofi-Pasteur.

Additional information

Funding

This paper was not funded.