Homologous and Heterologous Covid-19 Booster Vaccinations

Abstract

Background: Although the three vaccines against coronavirus disease 2019 (Covid-19) that have received emergency use authorization in the United States are highly effective, breakthrough infections are occurring. Data are needed on the serial use of homologous boosters (same as the primary vaccine) and heterologous boosters (different from the primary vaccine) in fully vaccinated recipients.

Methods: In this phase 1-2, open-label clinical trial conducted at 10 sites in the United States, adults who had completed a Covid-19 vaccine regimen at least 12 weeks earlier and had no reported history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection received a booster injection with one of three vaccines: mRNA-1273 (Moderna) at a dose of 100 μg, Ad26.COV2.S (Johnson & Johnson-Janssen) at a dose of 5×10¹⁰ virus particles, or BNT162b2 (Pfizer-BioNTech) at a dose of 30 μg. The primary end points were safety, reactogenicity, and humoral immunogenicity on trial days 15 and 29.

Results: Of the 458 participants who were enrolled in the trial, 154 received mRNA-1273, 150 received Ad26.COV2.S, and 153 received BNT162b2 as booster vaccines; 1 participant did not receive the assigned vaccine. Reactogenicity was similar to that reported for the primary series. More than half the recipients reported having injection-site pain, malaise, headache, or myalgia. For all combinations, antibody neutralizing titers against a SARS-CoV-2 D614G pseudovirus increased by a factor of 4 to 73, and binding titers increased by a factor of 5 to 55. Homologous boosters increased neutralizing antibody titers by a factor of 4 to 20, whereas heterologous boosters increased titers by a factor of 6 to 73. Spike-specific T-cell responses increased in all but the homologous Ad26.COV2.S-boosted subgroup. CD8+ T-cell levels were more durable in the Ad26.COV2.S-primed recipients, and heterologous boosting with the Ad26.COV2.S vaccine substantially increased spike-specific CD8+ T cells in the mRNA vaccine recipients.

Conclusions: Homologous and heterologous booster vaccines had an acceptable safety profile and were immunogenic in adults who had completed a primary Covid-19 vaccine regimen at least 12 weeks earlier. (Funded by the National Institute of Allergy and Infectious Diseases; DMID 21-0012 ClinicalTrials.gov number, NCT04889209.).

Figure 1. Reactogenicity of the Three Booster Vaccines against Covid-19, According to Primary Vaccine Regimen.

Shown are local (injection-site) and systemic reactions that were reported within 7 days after the administration of the mRNA-1273 (Panel A), Ad26.COV2.S (Panel B), and BNT162b2 (Panel C) boosters, according to the primary immunization regimen. Local and systemic reactions after the booster injection 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 Responses.

Shown are box plots of IgG binding antibody titers against SARS-CoV-2 and pseudovirus neutralizing antibody titers on day 1 (prebooster) and on days 15 and 29, according to whether the participant received the mRNA-1273 (Panel A), Ad26.COV2.S (Panel B), or BNT162b2 (Panel C) booster vaccine. The primary vaccination regimens are listed above the box plots. Binding antibody responses were measured against the wild-type (WA1 S-2P) control variant on a 4-plex electrochemiluminescence immunoassay analyzer (ECLIA), and neutralizing antibody titers were measured against the D614G mutation of the SARS-CoV-2 spike protein. Titers were bridged to international standards and reported as binding antibody units per milliliter and international units for the 50% inhibitory dose (IU50) per milliliter. Data points for individual participants are shown as gray circles. In each box plot, the horizontal line represents the median value, with the top and bottom of the box indicating the 75th percentile and 25th percentile, respectively; the whiskers indicate values that are within 1.5 times the interquartile range. The red dots represent participants who had detectable antibody against the SARS-CoV-2 nucleocapsid protein at enrollment, indicative of previous SARS-CoV-2 infection.

Figure 3. CD4+ and CD8+ T-Cell Responses.

Spike-specific T cells are shown in box plots before the administration of a homologous or heterologous booster vaccine on day 1 and after boosting on day 15. The boosters are shown at the top of each column, and the primary vaccines that each participant received are listed directly above each box plot. Circles indicate positive responses, and triangles indicate negative responses. Red symbols denote participants who had detectable antibody against the SARS-CoV-2 nucleocapsid protein at enrollment, indicative of previous SARS-CoV-2 infection. The responses are depicted as the background-subtracted percentage of spike-specific Th1 (interferon-γ, interleukin-2, or both) CD4+ T cells (top row), spike-specific Th2 (interleukin-4, interleukin-5, or interleukin-13) CD4+ T cells (middle row), and Th1 CD8+ T cells (bottom row). (Background subtraction refers to the subtraction of the values of the negative control sample from the peptide-stimulated sample.) The number of participants with a positive response among those tested is indicated as a fraction above each plot. Dashed lines link individual responses before and after the administration of the booster vaccine. The horizontal bar in each box indicates the median of all responses tested.