Heterogeneous Longitudinal Antibody Responses to Covid-19 mRNA Vaccination

Abstract

Background: Public health measures to stem the coronavirus disease 2019 (COVID-19) pandemic are challenged by social, economic, health status, and cultural disparities that facilitate disease transmission and amplify its severity. Prior pre-clinical biomedical technologic advances in nucleic acid-based vaccination enabled unprecedented speed of conceptualization, development, production, and widespread distribution of mRNA vaccines that target SARS-CoV-2's Spike (S) protein.

Design: Twenty-five female and male volunteer fulltime employees at the Providence VA Medical Center participated in this study to examine longitudinal antibody responses to the Moderna mRNA-1273 vaccine. IgM-S and IgG-S were measured in serum using the Abbott IgM-S-Qualitative and IgG2-S-Quantitative chemiluminescent assays.

Results: Peak IgM responses after Vaccine Dose #1 were delayed in 6 (24%) and absent in 7 (28%) participants. IgG2-S peak responses primarily occurred 40 to 44 days after Vaccine Dose #1, which was also 11 to 14 days after Vaccine Dose #2. However, subgroups exhibited Strong (n = 6; 24%), Normal (n = 13; 52%), or Weak (n = 6; 24%) peak level responses that differed significantly from each other (P < .005 or better). The post-peak IgG2-S levels declined progressively, and within 6 months reached the mean level measured 1 month after Vaccine Dose #1. Weak responders exhibited persistently low levels of IgG2-S. Variability in vaccine responsiveness was unrelated to age or gender.

Conclusion: Host responses to SARS-CoV-2-Spike mRNA vaccines vary in magnitude, duration and occurrence. This study raises concern about the lack of vaccine protection in as many as 8% of otherwise normal people, and the need for open dialog about future re-boosting requirements to ensure long-lasting immunity via mRNA vaccination versus natural infection.

Keywords: COVID-19; Spike protein; Veterans Administration; immune response; mRNA vaccine.

Figure 1.

Time course of (A) IgM-S and (B) IgG2-S responses to the Moderna mRNA-1273 vaccine in 25 volunteer participants. The left arrows correspond to the time of Vaccine Dose #1 (100 µg, i.m.) and the right arrows to Vaccine Dose #2 (100 µg, i.m.). Serum IgM-S and IgG2-S were measured at the plotted time points using the Abbott IgM-Spike Qualitative and IgG II-Spike Quantitative chemiluminescent assays. Analyses were performed on an Abbott Architect ci8200 Integrated Analyzer. Antibody levels are represented in arbitrary units (AU) based on standard curves. Data reflect mean (±SD) corresponding to (A) IgM-S or (B) IgG2-S levels (Y-axis) and the number of days after administrating Vaccine Dose #1 (See Table 1). Note the earlier IgM-S versus IgG2-S peak, and the progressive tapering of IgG2-S over a 6-month interval.

Figure 2.

Time course of individual IgM-S responses to Moderna mRNA-1273 among: (A) all participants, (B) normal responders, (C) late responders, and (D) latest responders. IgM-S levels (AU) are reflected on the Y-axis, and the number of days after Vaccine Dose #1 is represented on the X-axis. Data from non-responders are not shown. Day 0 (left arrow) corresponds to the day in which immunization was initiated. The right arrow corresponds to Vaccine Dose #2. Note the rightward shifts in IgM-S peaks from normal to the late and then the latest responders.

Figure 3.

IgM-S sub-group responder comparisons of the (A) timing of peak responses, (B) magnitude of responses, and (C) participants’ mean age. (A) Peak responses were significantly delayed in the late and latest responder groups relative to normal responders. (B) Late responders had significantly higher peak-levels of IgM-S relative to all other groups. (C) The mean ages did not differ significantly among the groups, including non-responders (none).

Figure 4.

Overall time-dependent trend in IgG-S responses. The mean levels of IgG2-S were calculated for measurements obtained at 30-day intervals after i.m. administration of Vaccine Dose #1. Day 30 was also the date of Vaccine Dose #2. Note that the highest protection levels were observed 60 and 90 days after vaccinations were initiated and 30 to 60 days after the second dose. One-way ANOVA with post hoc Tukey tests demonstrated significant differences from the 30-day time point. Furthermore, post hoc linear analysis was significant for progressive declines in mean IgG2-S over time, within 6 months of initial immunization (P < .0001).

Figure 5.

Time course of individual participant IgG2-S responses to the Moderna mRNA-1273 vaccine. The levels of IgG2-S (AU, arbitrary units) are reflected on the Y-axis and the days after Vaccine Dose #1 (0 time point) are represented on the X-axis for (A) all participants, (B) strong responders, (C) normal responders, and (D) weak responders. Note the higher IgG2-S peak levels in strong versus normal, and among strong and normal relative to weak responders.

Figure 6.

Subgroup differences in mean (±SD): (A) IgG2-S peak responses, (B) IgG2-S nadir responses, (C) number of days between Vaccine Dose #1 and peak responses, and (D) ages. The (A) peak and (B) nadir IgG2-S levels were significantly higher in strong compared with normal or weak responders. There were no significant inter-group differences in the (C) interval from vaccine administration to peak IgG2-S or (D) age.