key: cord-0994840-l9svmj30
authors: Amano, Masayuki; Maeda, Kenji; Tsuchiya, Kiyoto; Shimada, Shinya; Mitsuya, Hiroaki
title: Third-dose BNT162b2 vaccination elicits markedly high-level SARS-CoV-2-neutralizing antibodies in vaccinees who poorly responded to second dose in Japan
date: 2022-05-17
journal: J Infect Dis
DOI: 10.1093/infdis/jiac209
sha: db18c313a4e5b81097cd4e4c4f605fa2a9ba36da
doc_id: 994840
cord_uid: l9svmj30

nan

To the Editor -We read with great interest the article by Saciuk et al. demonstrating that, in a 1 retrospective cohort study in Israel, an additional dose of BNT162b2 vaccine 6 months after initial 2-dose 2 vaccination bolsters protection against infection, with a vaccine effectiveness of 89% as assessed during 3

August-October 2021, when the majority of infection was due to the Delta variant [1] . Recent SARS-4

CoV-2 studies using pseudovirus have shown that 3 rd -dose of BNT162b2 well elicits neutralizing 5 antibodies against VOCs (variants of concern) including the Omicron (B. In the present prospective study enrolling 225 health care workers (see demographic 10 characteristics in Supplementary Table 1) , who received 3-doses of BNT162b2 in Japan, we 11 consecutively determined SARS-CoV-2 neutralizing activity (NT 50 ) of their sera using VeroE6 TMPRSS2 12 cells over 300 days following the 1 st -dose and its kinetics/profiles, which is the continuation of our 13 previous study [6] . We also determined NT 50 s of selected sera using VeroE6 TMPRSS2 and HeLa hACE2-TMPRSS2 14 cells against infectious variants of concern VOCs including Delta and Omicrons (BA.1 and BA.2), whose 15 emergence has been associated with a steep increase in COVID-19 cases and hospitalizations 16 (experimental details are provided in the Methods section of Supplementary materials). 17

There was significant neutralizing activity on day-28 post-1 st dose (NT 50 =501 at one-week post-18 2 nd dose), while there was a continual decrease until day-280. NT 50 values further decreased to 51 by day-19 280 when ~85% of the participants had NT 50 values of <100 and ~36% had less than 20 NT 50 or 20 undetectable (Supplementary Figure 1) . However, 2 weeks after 3 rd -dose administration (205 21 participants [91.1%] had remained in the cohort on day-300), there was a substantial rise in neutralizing 22 activity, achieving an average NT 50 of 3,531. There was a concern that individuals who poorly responded 23 to 2 nd -dose might again fail to produce sufficient neutralizing antibodies. Therefore, we specifically 24 determined neutralization activity in vaccinees, who had achieved the bottom10% levels of neutralization 25 following the 2 nd -dose (n=22, average-NT 50 =110 on day-28; an inset of Supplementary Figure 1) . 26

Notably, by day-300, all those low responders achieved markedly greater levels of neutralizing activity 1 with the average-NT 50 of 2,341 ( Table 1 , range 482-9,113 in VeroE6 TMPRSS2 ). In HeLa hACE2+TMPRSS2 cells, 2 sera from those low responders substantially neutralized SARS-CoV-2 05-2N , Alpha, Beta, Gamma, and 3

Delta (geometric mean [gMean]-NT 50 =1,777, 1,350, 480, 1,015, and 959, respectively), but had only 4 marginal activity against Omicron/BA.1 with gMean-NT 50 being 52 (range ≤ 20-197; Table 1 CoV-2 05-2N and 6 VOCs were determined in cell-based assays using each SARS-CoV-2 strain and VeroE6 TMPRSS2 cells or 

Effectiveness of a Third Dose of BNT162b2 mRNA Vaccine

mRNA-based COVID-19 vaccine boosters 4 induce neutralizing immunity against SARS-CoV-2 Omicron variant

mRNA booster immunization elicits potent neutralizing 6 serum activity against the SARS-CoV-2 Omicron variant

Durability of omicron-neutralising serum activity after 8 mRNA booster immunisation in older adults

Rapid spread of SARS-CoV-2 Omicron subvariant BA