Safety and immunogenicity of SARS-CoV-2 variant mRNA vaccine boosters in healthy adults: an interim analysis

Abstract

The emergence of SARS-CoV-2 variants of concern (VOCs) and variants of interest (VOIs) with decreased susceptibility to neutralization has generated interest in assessments of booster doses and variant-specific vaccines. Clinical trial participants who received a two-dose primary series of the COVID-19 vaccine mRNA-1273 approximately 6 months earlier entered an open-label phase 2a study ( NCT04405076 ) to evaluate the primary objectives of safety and immunogenicity of a single booster dose of mRNA-1273 or variant-modified mRNAs, including multivalent mRNA-1273.211. As the trial is currently ongoing, this exploratory interim analysis includes preliminary descriptive results only of four booster groups (n = 20 per group). Immediately before the booster dose, neutralizing antibodies against wild-type D614G virus had waned (P < 0.0001) relative to peak titers against wild-type D614G measured 1 month after the primary series, and neutralization titers against B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta) VOCs were either low or undetectable. Both the mRNA-1273 booster and variant-modified boosters were safe and well-tolerated. All boosters, including mRNA-1273, numerically increased neutralization titers against the wild-type D614G virus compared to peak titers against wild-type D614G measured 1 month after the primary series; significant increases were observed for mRNA-1273 and mRNA-1273.211 (P < 0.0001). In addition, all boosters increased neutralization titers against key VOCs and VOIs, including B.1.351, P.1. and B.1.617.2, that were statistically equivalent to peak titers measured after the primary vaccine series against wild-type D614G virus, with superior titers against some VOIs. This trial is ongoing.

Fig. 1. Participant flow through the mRNA-1273 booster and mRNA-1273 variant booster cohorts.

In the mRNA-1273 booster phase, 20 participants who had received two injections of 100-μg mRNA-1273 completed the blinded phase and who went on to receive a single booster dose of 50-μg mRNA-1273 were selected for this preliminary analysis, with selection based on completion of day 15 visit assessments and immunogenicity sample availability. In the mRNA-1273 variant booster phase, enrollment was site specific and was based on predefined inclusion/exclusion criteria. Administration of booster doses occurred in a sequential manner (mRNA-1273 variant booster phase, which included the mRNA-1273.351 (50 µg) cohort; the mRNA-1273.211 (50 µg) cohort; and the mRNA-1273.351 (20 µg) cohort). ^aUnblinded or not unblinded to assigned treatment in the blinded portion of the phase 2a mRNA-1273 trial. ^bFifteen participants declined to receive a booster. ^cThirteen participants declined to receive a booster. ^dTwenty-two participants declined to receive an mRNA-1273 primary vaccination.

Fig. 2. ARs within 7 d after booster dose.

The percentage of participants who reported local (a) and systemic (b) ARs is shown for 20 participants who received a booster dose of mRNA-1273 (50 µg), 19 participants who received a booster dose of mRNA-1273.351 (20 µg), 19 participants who received a booster dose of mRNA-1273.351 (50 µg) and 20 participants who received a booster dose of mRNA-1273.211 (50 µg). One participant each in the mRNA-1273.351 50-µg and 20-µg groups did not report results for solicited ARs and were excluded from the analysis.

Fig. 3. Neutralization of wild-type D614G and B.1.351 by participant serum collected immediately before and after boosters, as measured by the lentiviral-based PsVN assay.

Wild-type D614G neutralization (a) and B.1.351 neutralization (b) in a validated recombinant lentivirus-based SARS-CoV-2 pseudovirus assay by serum from participants (n = 20 participants per booster cohort). Sera samples were collected immediately before receiving a booster (day 1) and on days 15 and 29 after the booster dose of mRNA-1273 (50 µg), mRNA-1273.351 (50 or 20 µg) or mRNA-1273.211 (50 µg). Participant sera in the mRNA-1273 (50 µg) booster group were not assessed in the B.1.351 assay. Data are presented as the geometric mean neutralizing antibody titers with 95% confidence intervals. The titers for individual participants are indicated with circles. The fold increases in titers measured at days 15 and 29 versus titers measured before the booster dose are shown. The horizonal dotted lines indicate the LLOQ. Generalized linear model was used to compare neutralization titers among groups; log₁₀ titer was regressed on group, and an individual-specific random effect was included to account for individual specific variability. Two-sided t-test was used for post hoc group comparisons. Sidak’s method was used to adjust the P values for multiple comparisons. Statistical significance was determined at α < 0.01. ****P < 0.0001; ***P < 0.001; **P < 0.01; *P < 0.05. NAb, neutralizing antibody.

Fig. 4. Neutralization of wild-type D614G and variants by participant serum collected 1 month after primary vaccination series and before and after boosters, as measured by the VSV-based PsVN assay.

Sera samples were collected 1 month after the primary series, immediately before receiving the booster dose (6 months after the primary vaccination series) and 2 weeks after the 50-µg booster dose of mRNA-1273 (a), mRNA-1273.351 (b) or mRNA-1273.211 (c). n = 20 for wild-type D614G, B.1.351 and P.1 and n = 11 for B.1.427/B.1.429, B.1.526, B.1.617.1 and B.1.617.2. d, Neutralization of wild-type D614G 1 month after the primary series and neutralization of wild-type D614G, B.1.617.1 and B.1.617.2 immediately before the booster dose from sera samples collected from a subset of participants in the mRNA-1273 booster group (D614G, n = 20; B.1.617.1, n = 11; B.1.617.2, n = 11). In a–d, the GMTs against the wild-type D614G and variants measured in participants before the booster dose or 2 weeks after the booster dose were evaluated versus peak titers measured against the wild-type D614G 1 month after the primary vaccination series. Data are presented as the geometric mean neutralizing antibody titers with 95% confidence intervals. The GMT fold change versus the peak titers against the wild-type D614G virus after the primary vaccination series are shown, with red indicating fold drop and blue indicating fold rise. Results from individual participants are represented as dots on each figure. For all panels, blue colored dots indicate participants whose samples were tested (n = 11), and white dots indicate the remaining participants whose samples were not tested (n = 9). The horizonal dotted line indicates the LLOQ; the solid gray line indicates the within-cohort GMT benchmark. Generalized linear model was used to compare neutralization titers among groups; log₁₀ titer was regressed on group, and an individual-specific random effect was included to account for individual specific variability. Two-sided t-test was used for post hoc group comparisons. Sidak’s method was used to adjust the P values for multiple comparisons. Statistical significance was determined at α < 0.01. ****P < 0.0001; ***P < 0.001; **P < 0.01; *P < 0.05. NAb, neutralizing antibody; NS, not significant.