Heterologous SARS-CoV-2 Booster Vaccinations - Preliminary Report

Abstract

Background: While Coronavirus disease 2019 (Covid-19) vaccines are highly effective, breakthrough infections are occurring. Booster vaccinations have recently received emergency use authorization (EUA) for certain populations but are restricted to homologous mRNA vaccines. We evaluated homologous and heterologous booster vaccination in persons who had received an EUA Covid-19 vaccine regimen.

Methods: In this phase 1/2 open-label clinical trial conducted at ten U.S. sites, adults who received one of three EUA Covid-19 vaccines at least 12 weeks prior to enrollment and had no reported history of SARS-CoV-2 infection received a booster injection with one of three vaccines (Moderna mRNA-1273 100-μg, Janssen Ad26.COV2.S 5×10¹⁰ virus particles, or Pfizer-BioNTech BNT162b2 30-μg; nine combinations). The primary outcomes were safety, reactogenicity, and humoral immunogenicity on study days 15 and 29.

Results: 458 individuals were enrolled: 154 received mRNA-1273, 150 received Ad26.CoV2.S, and 153 received BNT162b2 booster vaccines. Reactogenicity was similar to that reported for the primary series. Injection site pain, malaise, headache, and myalgia occurred in more than half the participants. Booster vaccines increased the neutralizing activity against a D614G pseudovirus (4.2-76-fold) and binding antibody titers (4.6-56-fold) for all combinations; homologous boost increased neutralizing antibody titers 4.2-20-fold whereas heterologous boost increased titers 6.2-76-fold. Day 15 neutralizing and binding antibody titers varied by 28.7-fold and 20.9-fold, respectively, across the nine prime-boost combinations.

Conclusion: Homologous and heterologous booster vaccinations were well-tolerated and immunogenic in adults who completed a primary Covid-19 vaccine regimen at least 12 weeks earlier.

Keywords: Booster; Covid-19; SARS-CoV-2; Vaccine; antibody; mRNA; recombinant adenovirus.

Figure 1 |. Reactogenicity

Injection site and systemic reactions reported within 7 days after administration of the Ad26.COV2.S, mRNA-1273, and BNT162b2 boosts are depicted by primary EUA immunization regimen. Local and systemic reactions following boost were graded as mild (does not interfere with activity), moderate (interferes with activity) or severe (prevents daily activity).

Figure 2 |. Binding Antibody and Neutralizing Antibody Titers

SARS-CoV-2 IgG binding antibody titers (A-C) and pseudovirus neutralization IU50/mL titers (D-F) at Study Day 1 (baseline), Study Day 15 (post-boost), and Study Day 29 (subset analysis; day 29 data not available for all groups). Binding antibody responses to wildtype (S-2P-WA-1 control), as measured by 4-plex ECLIA, and neutralizing antibody (NAb) levels to D614G, grouped by primary EUA immunization regimen (Ad26.COV2.S, mRNA-1273 and BNT162b2) and booster dosing are depicted. Titers were bridged to international standards and reported as Binding Antibody Units/mL and International Units (IU) 50% inhibitory dose/mL (IU50/mL). Individual values are shown as grey circles. Box plots represent median (horizontal line within the box) and 25^th and 75^th percentiles (lower and upper borders of the box), and the whiskers drawn to the value nearest to, but within, 1.5 times the interquartile range below and above the 25^th and 75^th percentile, respectively. The red dots represent participants possessing detectable antibody to the SARS-CoV-2 nucleocapsid protein at enrollment, indicative of a prior SARS-CoV-2 infection.