SARS-CoV-2 antibody response in persons with natural infection in the past

To the editor:

Whether persons already infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) should be vaccinated is unclear. Only a few studies have shown that vaccines previously infected with SARS-CoV-2 had a significantly higher antibody response than previously uninfected vaccines.^1-4 In an observational group study, we enrolled 100 health workers, including 38 (9 men and 29 women) with a documented history of SARS-CoV-2 infection (mean duration between infection and vaccination, 111 days). The mean age of these previously infected participants was 35.1 years (95% confidence interval [CI], 31.7 to 38.6). Our study also included 62 participants (25 men and 37 women) who had not been infected before. The mean age of the participants was 44.7 years (95% CI, 41.0 to 47.6).

Both groups of participants received the messenger RNA vaccine BNT162b2 (Pfizer – BioNTech). Serum samples were obtained 10 days after the administration of the first dose from the previously infected participants and 10 days after the administration of the second dose from the previously uninfected participants. Thereafter, all participants were screened for the presence of specific anti-SARS-CoV-2-spike IgG by means of an immunoassay for chemiluminescence microparticles.

Figure 1. Figure 1. Immune response in participants with or without previous SARS-CoV-2 infection.

Titers of circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) anti-spike IgG antibodies (panel A) and neutralization of SARS-CoV-2 anti-spike IgG antibodies (panel B) are shown in serum samples obtained from previously infected participants after receiving a single dose of vaccine and in samples obtained from previously uninfected participants after receiving a second dose of vaccine. Differences in circulation (panel C) and neutralization (panel D) IgG antibodies in samples obtained from previously infected participants were evaluated according to the duration of natural infection until vaccination (1 to 2 months,> 2 months to 3 months, or> 3 months ). In each box-and-mustache plot, the horizontal line represents the median, the top and bottom of the subject are the interquartile range and the mustache beard the minimum and maximum values. GMT indicates geometric mean titer.

No significant difference in circulating anti-spike IgG antibody titers was observed between the samples of previously infected participants (mean level, 20,120 arbitrary units per milliliter; 95% AI, 16,400 to 23,800) and those of previously uninfected participants (mean level, 22,639 arbitrary units per milliliter; 95% AI, 19,400 to 25,900) (median levels are shown in Figure 1A). Circulating IgG antibodies against nails were not detected in only one participant who was previously infected; that participant does not have an antibody response to natural infection with SARS-CoV-2.

The same serum samples were also analyzed for the presence of specific anti-SARS-CoV-2 neutralizing antibodies. We observed a difference in levels of neutralizing antibodies between samples from the previously infected participants (geometric mean titer, 569; 95% CI, 467 to 670) and those from the previously uninfected participants (geometric mean titer, 118; 95% CI , 85 to 152) (P <0.001) (median levels are shown in Figure 1B). No significant differences were observed between the titers of the previously infected and the previously uninfected participants according to age (Fig. S1 in the supplementary appendix, available with the full text of this letter at NEJM.org) or gender (data not shown) .

The previously infected participants were divided into three groups according to the time elapsed from infection to vaccination: 1 to 2 months (8 participants), more than 2 months to 3 months (17 participants) and more than 3 months (12 participants)) . The previously infected patient, in whom circulating antibodies to IgG antibodies were not detected, was not included in this categorization. The circulating IgG mean titers differed between the group vaccinated after 1 to 2 months and the group vaccinated more than 2 months to 3 months after natural infection (mean level, 15,837 random units per milliliter [95% CI, 11,265 to 20,410] versus 21,450 random units per milliliter [95% CI, 15,377 to 27,523]) (median levels are shown in Figure 1C); However, as the number of participants was limited, there can be no real distinction. No further significant difference was observed between the group of participants vaccinated longer than 2 months to 3 months and the group vaccinated more than 3 months after infection (mean level, 21 090 arbitrary units per milliliter [95% CI, 14,702 to 27,477]).

The differences between the three groups were more pronounced with respect to levels of neutralizing antibodies, with geometric mean titers ranging from 437 (95% CI, 231 to 643) in participants 1 to 2 months after infection to 559 (95% CI, 389 vaccinated) to 730) in those vaccinated more than 2 months to 3 months after infection up to 694 (95% AI, 565 to 823) in those vaccinated more than 3 months after infection (median levels are shown in Figure 1D). Although these findings indicate that the booster response was more effective when the vaccine was administered more than 3 months after infection, there is not enough information available to draw a definitive conclusion.

The most remarkable finding of this study was the significantly lower neutralizing antibody titer after administration of a second dose of vaccine in previously uninfected patients, than the titer after only a single dose of vaccine in previously infected participants. It is unclear how the neutralizing antibody titers affect the ability of the host to transmit the virus. These findings provide evidence that after administration of a single dose of vaccine, the humoral response to SARS-CoV-2 in individuals with a history of SARS-CoV-2 infection is greater than the response in previously uninfected participants receiving a second dose.

Gabriele Anichini, MS
Chiara Terrosi, MS
Claudia Gandolfo, Ph.D.
Gianni Gori Savellini, Ph.D.
University of Siena, Siena, Italy

Simonetta Fabrizi, Managing Director
Giovanni B. Miceli, Managing Director
Santa Maria alle Scotte University Hospital, Siena, Italy

M. Grazia Cusi, Ph.D.
University of Siena, Siena, Italy
[email protected]

This letter was published on April 14, 2021 on NEJM.org.