Waning Immune Humoral Response to BNT162b2 Covid-19 Vaccine over 6 Months | NEJM – nejm.org


Study Population and Serologic Assays

Recruitment of Participants, Testing, and Follow-up.

This study involved a prospective cohort of health care workers who had received the BNT162b2 vaccine and underwent at least one serologic assay after receipt of the second dose of vaccine. During the study period (December 19, 2020, to July 9, 2021), participants were followed monthly for 6 months after receipt of the second dose. PCR denotes polymerase chain reaction, and SARS-CoV-2 severe acute respiratory syndrome coronavirus 2.

The study was conducted from December 19, 2020, to July 9, 2021. Of the 12,603 vaccinated health care workers who were eligible for the study, 4868 were recruited for study participation (Figure 1). During the study period, 20 participants had a breakthrough SARS-CoV-2 infection (defined as a positive PCR result for SARS-CoV-2), and 5 had a positive anti-N result. A total of 14,736 IgG assays and 4521 neutralizing antibody assays were performed. The numbers of persons with repeated IgG tests and neutralizing antibody assays are shown in Figure 1. IgG levels were evaluated at least once for all study participants during the 6 months of follow-up and at least twice for 2631 participants (54.0%). The neutralizing antibody subgroup included 1269 participants (26.1%) who underwent at least one neutralizing antibody test; 955 of these participants (75.3%) were tested at least twice. Data on age and sex were available for all study participants. Overall, 3808 participants (78.2%) responded to the computer-based questionnaire and were included in the mixed-model analysis.

The demographic characteristics and data on coexisting conditions in the study participants are provided in Table S1, in both the overall population and the neutralizing antibody subgroup. The mean (±SD) age of the participants was 46.9±13.7 years in the overall population and 52.7±14.2 years in the neutralizing antibody subgroup. The distributions of the demographic characteristics and coexisting conditions among the participants according to study period and IgG and neutralizing antibody assays are provided in Tables S4 and S5.

SARS-CoV-2 Antibody Kinetics after Receipt of Second Vaccine Dose

Distribution of Antibodies 6 Months after Receipt of Second Dose of the BNT162b2 Vaccine.

Panels A and B show the geometric mean titers (GMTs) of IgG and neutralizing antibody, respectively, in the entire study population, and Panels C through F show GMTs according to age group and sex. Antibodies were tested monthly throughout seven periods after receipt of the second dose of vaccine. Dots represent individual observed serum samples. The dashed line in each panel indicates the cutoff for diagnostic positivity. 𝙸 bars indicate 95% confidence intervals. RBD denotes receptor-binding domain.

Antibody response and kinetics were assessed for 6 months after receipt of the second vaccine dose (Figure 2A and 2B and S1 and Table S6). The highest titers after the receipt of the second vaccine dose (peak) were observed during days 4 through 30, so this was defined as the peak period. The expected geometric mean titer (GMT) for IgG for the peak period, expressed as a sample-to-cutoff ratio, was 29.3 (95% confidence interval [CI], 28.7 to 29.8). A substantial reduction in the IgG level each month, which culminated in a decrease by a factor of 18.3 after 6 months, was observed. Neutralizing antibody titers also decreased significantly, with a decrease by a factor of 3.9 from the peak to the end of study period 2, but the decrease from the start of period 3 onward was much slower, with an overall decrease by a factor of 1.2 during periods 3 through 6. The GMT of neutralizing antibody, expressed as a 50% neutralization titer, was 557.1 (95% CI, 510.8 to 607.7) in the peak period and decreased to 119.4 (95% CI, 112.0 to 127.3) in period 6.

Differential Decay According to Age and Sex

IgG and neutralizing antibody kinetics showed differences in immunogenicity according to age group and sex (Figure 2C through 2F). The rate of IgG decay in all subgroups defined according to age and sex was constant throughout the 6-month period, whereas neutralization was substantially reduced up to period 3, followed by a slower decrease thereafter. Participants 65 years of age or older had lower IgG and neutralizing antibody levels than persons 18 to less than 45 years of age during the peak period and also had a greater decrease, up to approximately 3 months (end of period 2), in the neutralizing antibody titer (Figure 2C and 2D, and see Supplementary Results Sections S1 and S2).

Predictors of Peak and End-of-Study Antibody Titers

In the peak and end-of-study periods, significantly lower IgG titers were associated with older age, male sex, the presence of two or more coexisting conditions (i.e., hypertension, diabetes, dyslipidemia, or heart, lung, kidney, or liver disease), the presence of autoimmune disease, and the presence of immunosuppression. Significantly lower neutralizing antibody titers were associated with older age, male sex, and the presence of immunosuppression in both periods, and significantly higher neutralizing antibody titers were associated with a BMI of 30 or higher (obesity) as compared with a BMI of less than 30 in both study periods. Our results show that although the IgG and neutralizing antibody titers were significantly lower in participants with two or more specific coexisting conditions than in those with no specific coexisting condition during the peak period, no significant differences in neutralizing antibody titers were observed at the end of study. In addition, participants with autoimmune disease had a significantly lower IgG titer but not neutralizing antibody titer during both the peak and end-of-study periods than did those without autoimmune disease. An age-by-sex interaction was found; the difference by which the titers in men 45 years of age or older were lower than the titers in men younger than 45 years of age was larger than the difference between the corresponding female groups.

Mixed-Model Analysis of Variables Associated with IgG and Neutralizing Antibody Titers after Receipt of the Second Vaccine Dose.

At the end of study, the mixed-model analysis showed decreases in IgG and neutralizing antibody concentrations of 38% and 42%, respectively, among persons 65 years of age or older as compared with participants 18 to less than 45 years of age and of 37% and 46%, respectively, among men 65 years of age or older as compared with women in the same age group (Table 1). Participants with immunosuppression had decreases in the IgG and neutralizing antibody concentrations of 65% and 70%, respectively, as compared with participants without immunosuppression. Obese participants (those with a BMI of ≥30) had a 31% increase in neutralizing antibody concentrations as compared with nonobese participants (Table 1).

For IgG levels, the correlation between individual participants’ peak levels and their slopes of the decrease was positive but weak (0.17; 95% CI, 0.11 to 0.24); the rates of decay were not strongly related to initial levels. However, for neutralizing antibody, the correlation was strongly negative (−0.63; 95% CI, −0.70 to −0.55). After adjustment for other factors, participants with a higher initial level tended to have a decrease that was faster up to approximately 70 days after receipt of the second dose. Beyond that time, rates of decay were modest and did not vary much among participants.

Probability of Having a Titer below Different Neutralizing Antibody Titers at 175 Days after Receipt of the Second Vaccine Dose, According to Sex and Age.

We used the mixed model to predict the probability in different subgroups of reaching a neutralizing antibody titer lower than the test cutoff for diagnostic positivity (i.e., <16) by 6 months after receipt of the second dose. We also used the model to predict the probability of a decrease to below different neutralizing antibody titers (<32, <64, <128, or <256) (Table 2). Among healthy women and men in the three age groups (18 to <45 years, 45 to <65 years, and ≥65 years of age), the probability of having a neutralizing antibody titer of less than 256 at 175 days after receipt of the second dose were as follows: 0.68, 0.79, and 0.81, respectively, among women and 0.75, 0.89, and 0.92, respectively, among men. The probability of having a neutralizing antibody titer of less than 16 in these three age groups (18 to <45 years, 45 to <65 years, and ≥65 years of age) were as follows: 0.02, 0.05, and 0.06, respectively, among women and 0.04, 0.11, and 0.15, respectively, among men. Overall (regardless of sex and age group), obese participants were at lower risk for having lower neutralizing antibody titers than nonobese participants. Participants with immunosuppression were more likely than healthy participants to have a below-average neutralizing antibody titer (Table 2).

Correlation between IgG and Neutralizing Antibody Levels

We assessed the correlation between IgG and neutralizing antibody levels. Although a strong correlation between IgG and neutralizing antibody titers was maintained throughout the 6 months after receipt of the second dose of vaccine (Spearman’s rank correlation between 0.68 and 0.75) (Fig. S2), the regression relationship between the IgG and neutralizing antibody levels depended on the time since the second dose of vaccine, a finding that was probably due to the different kinetics between IgG and neutralizing antibody levels (Figure 2).

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