Decline of immune humoral response after BNT162b2 vaccine.

Dear editor,

In this Journal, Tre-Hardy and coll. recently reported waning of anti-S-antibody response to mRNA −1273 vaccine in health care workers. In a similar cohort, we describe the time-dependent response of humoral immunity after BNT162b2 vaccine. The disproportionate number of deaths caused by SARS-CoV-2 pandemic has been substantially curtailed by the early development of highly efficient vaccines, but scarce data are available on the kinetics of antibodies following mRNA vaccines. IgG antibodies directed against Sars-CoV2 spike-protein (SP) are strongly correlated to neutralizing antibodies and can be considered a surrogate marker of immune response to vaccine. Our study (ClinicalTrials.gov ID # NCT04733807) initially planned for a follow up of 12 months was stopped prematurely because the Italian Government scheduled a booster dose.

The study cohort included 679 participants out of 683 health care workers (four subjects refused vaccination) of our hospital.

Here, we report serum anti-SP IgG measured at 6, 15, and 28 weeks after BNT162b2 vaccine using SARS-CoV-2 IgG II Quant kit on an Architect system (Abbott).

Fifteen percent of the study population was affected by one of the following diseases: high blood pressure (6.7%), asthma (2.2%), dyslipidemia (2.0%), diabetes (1.7%), cardiovascular disease (0.6%), or took steroids (1.3%). Sixty-five subjects had Covid-19 either before, or after starting vaccination, and eventually developed mild symptoms but didn't require hospitalization. Among them, 28 participants received only one vaccine dose, which was related to initial Government guidelines in a time context of challenges to the supply chain and belief that a single-dose administration might suffice for individuals recovered from prior infection.

The time evolution of Ab titer in response to vaccination is shown in Fig. 1 .

Fig. 1

Decay of anti-SP Ab in the population. Levels of serum anti-SP IgG (arbitrary units, median ± IQR) in the whole population at 6, 15, and 28 weeks of follow up; inset, percent decay.

In a subset of participants (n = 27) in whom we obtained serum samples three weeks after vaccination the resulting anti-SP IgG titer was 1026 [384-1291] (median, IQ range), suggesting that peak immunity occurred approximately at six weeks after vaccination when the Ab titer was 8485 [4510-14,490] (median, IQ range). At peak immunity anti-SP IgG titer range was wide, spanning more than two orders of magnitude (min 141, max 65,667 AU).

A progressive reduction of anti-SP IgG was observed over time, with a sharp decay at 15 weeks (−68%), to reach a residual value of about 18% at 28 weeks, and the calculated half-life was 3.8 months. Anti-SP IgG titer at 15 and 28 weeks highly correlated with the titer at 6 weeks (week 15 vs. 6, rho = 0.875; week 28 vs. 6, rho = 0.691), indicating that the degree of decay was very dependent from the peak immunity value.

The profile of anti-SP IgG response as function of vaccination status and/or prior infection is reported in Fig. 2 .

Fig. 2

Anti-SP IgG titer in study participants as function of vaccination status and Covid-19 positivity. Participants with incomplete vaccination that resulted positive to Covid-19 (n = 28, red line) had a lower anti-SP IgG titer at peak immunity (log transformed value, mean, 95% CI), but not at 28 weeks, compared to participants with full vaccination status (2 jabs) (n = 614, green line). Among participants with complete vaccination, those with history of Covid-19 (n = 37, blue line) had higher anti-SP IgG titer at peak vaccination and persistently higher titer throughout the study period compared to Covid-19 negative ones.

On one hand, subjects with prior infection and incomplete vaccination showed a lower level of anti-SP IgG at peak immunity compared to subjects that were fully vaccinated. On the other hand, among participants that were fully vaccinated, subjects with prior infection showed a consistently higher anti-SP IgG titer at peak immunity that persisted higher throughout the study period, compared to the people without prior infection.

A mixed-effects model was applied to estimate the effect of vaccination status - i.e., complete/incomplete vaccination and prior infection, along with age, gender, and clinical status on the logarithm of anti-SP IgG response. A subject-specific random intercept was used to consider dependence arising from repeated measures on the same subject.

Anti-SP IgG response was significantly higher at week 6 compared to both week 15 (β = −1.133, 95% CI: −1.179; −1.088, p < 0.0001) and week 28 (β = −1.974, 95% CI: −2.019; −1.928, p < 0.0001), negatively correlated with age (β −0.011, 95% CI: −0.016; −0.006, p < 0.0001), and resulted higher in women than in males (β 0.185, 95% CI: 0.066; 0.304 p = 0.0025). Meanwhile disease status appeared to have no significant effect. In subjects with previous Covid-19 anti-SP IgG titer was higher in those with full vaccination compared to those with incomplete vaccination (β 1.311, 95% CI 0.966 – 1.656, p < 0.0001); and was higher in subjects fully vaccinated Covid-19 negative compared to incompletely vaccinated Covid-19 positive subjects (β 0.338, 95% CI 0.114 – 0.663, p = 0.0058). In this study conducted in vaccinees with mRNA BNT162b2, we found a wide range in antibody titer at peak immunity, and a substantially waning of antibody titers within 28 weeks of follow up, in agreement with previous data on mRNA vaccines. ,

Given the challenges derived by the global demand of vaccines, the need of implementing vaccination status with booster doses, the occurrence of SARS-CoV2 variants with development of new/modified mRNA vaccines, surrogate markers of vaccine efficacy are highly sought. Our study indicates that the lowest Ab response is observed in subjects with one jab vaccination and prior infection, while the highest Ab response was observed in fully vaccinated subjects with prior infection, whereas fully vaccinated subjects without infection positioned in the middle. There was, however, a comparable decay rate of antibodies in infected versus non-infected subjects that is in line with a recent report.

A recent study on mRNA-1273 vaccine, reported strong evidence that circulating antibodies -including neutralizing and binding antibodies, are directly correlated with vaccine efficacy, and inversely correlated with Covid-19 risk. Analytical methods for the measurement of anti-SP IgG titer in high throughput settings are already available. Therefore, anti-SP IgG may be used as a surrogate marker in assessing the status of protection against Covid-19 disease in the single individual, especially in a supply-limited environment, once appropriate cut-off values and inter-laboratory harmonization are identified by specifically addressed studies.