key: cord-0702167-8235095p
authors: Bi, Xiuqiong; Takayama, Tomoko; Tokoro, Masaharu; Mizuno, Tetsushi; Hara, Akinori; Nakamura, Hiroyuki; Oe, Hiroyasu; Nagamatsu, Soichiro; Kitano, Yoshiki; Ichimura, Hiroshi
title: Longer Intervals before Vaccination Increase Spike Antibody Titers in Individuals Previously Infected with SARS-CoV-2
date: 2022-04-06
journal: Microbiol Spectr
DOI: 10.1128/spectrum.00238-22
sha: 33668cf789ff15b8a4727e3d8a1d6c00ca91c5bc
doc_id: 702167
cord_uid: 8235095p

nan

W e investigated the impact of the interval between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and vaccination on SARS-CoV-2 spike receptor-binding domain antibody (RBD-Ab) titer in individuals previously infected with SARS-CoV-2. After two doses of a vaccine, RBD-Ab titer was significantly higher in individuals with SARS-CoV-2 infection history than those without the history, and the interval between SARS-CoV-2 infection and the vaccination was the only independent predictor for the RBD-Ab titer in those with the infection history. These results suggest that longer intervals between SARS-CoV-2 infection and vaccination may promote a better humoral immune response in individuals with past SARS-CoV-2 infection.

Vaccination against SARS-CoV-2 is recommended for individuals with SARS-CoV-2 infection history as well as those without the history to prevent SARS-CoV-2 reinfection/infection and its progression to severe disease (1-3). However, appropriate timing for the vaccination has not yet been established in individuals with past SARS-CoV-2 infection. In this study, we investigated the impact of the interval between SARS-CoV-2 infection and the vaccination on the antibody titer induced by the vaccine in individuals previously infected with SARS-CoV-2.

A total of 1,875 general residents of Ishikawa prefecture, Japan, who had received two doses of the SARS-CoV-2 vaccine voluntarily applied for this survey via the Internet from October 9 to October 15, 2021. Blood sample collection and a questionnaire were completed at Kanazawa University Hospital in Japan from October 25 to November 7, 2021. SARS-CoV-2 RBD-Ab and nucleocapsid antibody (NC-Ab) were detected by Elecsys Anti-SARS-CoV-2 S (S300) RUO and Elecsys Anti-SARS-CoV-2 (S300) RUO (Roche Diagnostics, IN, USA), respectively, and neutralizing antibody using the SARS-CoV-2 Surrogate Virus Neutralization Test kit (GenScript, NJ, USA).

Of the 1,875 participants, 1,869 (99.7%) were positive for RBD-Ab and 55 for NC-Ab. Of the 1,820 NC-Ab negatives, 3 had a SARS-CoV-2 RT-PCR-positive history. Therefore, 58 participants were considered to have been previously infected with SARS-CoV-2, 44 of whom reported their SARS-CoV-2 infection dates. All 44 participants with known infection dates received the second dose of vaccine 21 to 28 days after the first-dose vaccination, except two cases who received the second dose 59 and 66 days after the first vaccination due to infection with SARS-CoV-2 after the first vaccination and his work commitments, respectively. The other case infected with SARS-CoV-2 after the first vaccination received the second dose 21 days after the first vaccination.

The RBD-Ab titer was significantly higher in participants with SARS-CoV-2 infection history than in those without history of infection ( Fig. 1A ). Multivariable lineage regression analysis revealed that history of SARS-CoV-2 infection was an independent predictor of RBD-Ab titer, in addition to the type of vaccine (Pfizer or Moderna), age, gender, and days after vaccination. Notably, in the participants with a history of SARS-CoV-2 infection, the interval between SARS-CoV-2 infection and the second-dose vaccination was positively related to the RBD-Ab titer (P , 0.001; Fig. 1B) . Moreover, the interval between the SARS-CoV-2 infection and the vaccination was the only predictor of the RBD-Ab titer after adjusting for vaccine type, age, gender, and days after the second dose of vaccine in these participants (R = 0.676, adjusted R 2 = 0.385, P , 0.001). All 58 participants previously infected with SARS-CoV-2 had antibodies with an activity that inhibited RBD-receptor binding by more than 95%, except one who had the antibody with inhibition activity of 87.5% (RBD-Ab titer: 19,651 units/mL, 66 days between the first and second vaccination).

Therefore, we found that the RBD-Ab titer is significantly higher in the general Japanese population with a history of SARS-CoV-2 infection than in those without a history of infection. This observation is consistent with a previous report on Japanese healthcare workers (4) . Notably, in participants previously infected with SARS-CoV-2, the interval between SARS-CoV-2 infection and the vaccination was the only positive predictor of the RBD-Ab titer. Our findings indicate that the longer the interval between a past SARS-CoV-2 infection and the vaccination, the higher the RBD-Ab titer. This finding could be partially explained by previous findings that SARS-CoV-2 spike-specific memory B cells are more abundant 6 months post-symptomatic onset compared to 1 month (5) and remain relatively stable between 6 and 12 months after infection (6) . In addition, SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans (7). This is the first report to indicate that longer intervals between SARS-CoV-2 infection and vaccination may promote a better humoral immune response in individuals previously infected with SARS-CoV-2.

This study was funded by Ishikawa Prefecture and approved by Kanazawa University Ethics Committee.

Blood samples were collected after obtaining written informed consent. We declare no conflict of interest.

Coronavirus (COVID-19) vaccine

RBD-Abs) after the second dose of vaccine. (A) Box plots showing the RBD-Ab titer in participants with or without SARS-CoV-2 infection history (Mann-Whitney U test). (B) The interval between SARS-CoV-2 infection and the second vaccination was positively related to RBD-Ab titer (Spearman correlation). Open circles and diamonds represent the participants who received Pfizer's vaccine, closed circles represent those who received Moderna's vaccine, and open diamonds represent those

Labour and Welfare. 2022. COVID-19 vaccines

Spike antibody titers evaluation after a 2-dose regimen of BNT162b2 vaccination in healthcare workers previously infected with SARS-CoV-2

Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection

Naturally enhanced neutralizing breadth against SARS-CoV-2 one year after infection

SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans