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Commentary: Vaccines and COVID-19
From IAS COVID-19 Prevention: Significant Advances in a Global Vaccination Program

Released: March 18, 2021

Expiration: March 17, 2022

Kenneth Mayer
Kenneth Mayer, MD
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Significant progress in vaccine development and distribution has been achieved by the CoVPN (COVID-19 Vaccine Prevention Network) built upon the preexisting infrastructure of research partners and global networks, primarily focusing on HIV. These advances and breakthroughs to date have been the result of a remarkable collaboration and synergy including laboratories setting up protein platforms, statistical groups harmonizing trial designs and endpoints, and common data and safety monitoring boards. The focus has been to assess key technologies to develop multiple vaccines, recognizing the need to manufacture globally and have options for mechanism of action and scalability. To date, the main target for vaccines has been the SARS-CoV-2 spike protein. These have included protein vaccines including spike nanoparticle and soluble prefusion trimer, mRNA vaccines, and viral vector vaccines, particularly adenovirus. All of these technologies are making their mark and will be instrumental in returning to social normalcy.

An Extraordinary Effort to Date on Clinical Efficacy Trials
It is important to emphasize that 5 efficacy trials under the aegis of Operation Warp Speed involving at least 30,000 individuals each have been conducted or planned since July 2020. When the results of the BNT162b2 (Pfizer/BioNTech) and mRNA-1273 (Moderna) vaccines, both prefusion spike transcript vaccines, are compared, they are remarkably similar, lending confidence in the veracity of the data and efficacy of RNA technology. The Pfizer/BioNTech vaccine demonstrated a 95% vaccine effectiveness (VE) against symptomatic COVID-19 (94% in individuals older than 65 years) and the Moderna vaccine demonstrated a 94.5% VE against symptomatic COVID-19 with no difference in efficacy by age or ethnicity. Both were well tolerated. In addition, more recently, the preliminary data for the Ad.26.COV2.S (Janssen) 1-dose adenovirus-vector vaccine demonstrated 66% overall VE in preventing moderate or severe COVID-19. Data from large AZD1222 (AstraZeneca) and NVX-CoV2373 (Novavax) efficacy studies should be forthcoming soon that will further extend findings of smaller promising studies of the AstraZeneca and Novavax vaccines. The implications of the availability of multiple effective COVID-19 vaccines on clinical trials of new vaccine candidates may require head-to-head noninferiority (rather than placebo) studies and larger sample sizes as infection rates decrease.

Variants Are Changing the Game
After 10 months of perceived quiescence, we predictably began to see the emergence of viral variants. Two unique variants that have deservedly received the most attention are B.1.1.7 (first detected in the United Kingdom) and 501Y.V2, also known as B.1.157 (first detected in South Africa). Both have mutations in the receptor binding domain (RBD), associated with increased infectivity. Other mutations in the RBD and N terminal domain can potentially influence virus neutralization by monoclonal antibodies and immune responses generated by vaccines. The question of how well the sera from vaccinees neutralize the variants becomes a vital one. Data show that sera from vaccinees neutralize the United Kingdom variant well. The South African variant is a different picture, however, with most studies showing a 5-fold reduction in neutralization. Interim analysis from an NVX-CoV2373 (Novavax) nanoparticle vaccine study demonstrated very high efficacy in preventing symptomatic COVID-19 (VE: 89.3%) including the UK variant. Although it retained good efficacy in the South African variant, it was not at the same level (VE: 60.1% for HIV-negative participants and 49.4% for participants with HIV). The Janssen vaccine was studied in United States, Brazil, and South Africa demonstrating VE of 72% in the United States and Brazil and 57% in South Africa. Hence, we are likely seeing the effects of the additional mutations of the South African variant in escaping immune pressure. Other variants of interest include P.1 (first detected in Brazil), which shares similar mutations with the South African variant and has been associated with a high rate of reinfection in the city of Manaus, suggesting that immunity may not provide high levels of protection against some of the mutants, so boosters or modifications in vaccine formulations may be necessary.

Higher Antibody Responses Are Good but Not the Whole Story
Immunogenicity data from both the Pfizer/BioNTech and Moderna vaccines demonstrate an almost complete lack of neutralizing antibody prior to the second dose. It is this booster that appears to provide the robust and presumably durable immune response. Clinical efficacy, however, has been demonstrated after the first dose albeit to a lesser extent. Of importance, this extends to the prevention of severe disease and death. Some very promising data from the Janssen vaccine interim analysis shows that despite less of an antibody response compared with 2 doses of the Pfizer/BioNTech and Moderna vaccines and the variation of responses in South Africa compared to those in the United States and Brazil, efficacy was high in all countries for severe COVID-19 (VE: 85%) and death (VE: 100%). Thus, it is likely that correlates of immune protection may be a combination of antibody and T-cell responses.

In conclusion, we may need to reconfigure our thinking regarding how vaccines may affect the global pandemic. Although vaccines may have varying degrees of efficacy for prevention of COVID-19 disease, a rapid increase in vaccine coverage and improved molecular surveillance for early detection of problematic variants, which may require boosters that address viral evolution, should begin to allow us to return to our normal lives.

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