{"doi":"10.1093/infdis/jiac393","title":"Restoration of Neutralization Activity Against Omicron BA.2 and BA.5 in Older Adults and Individuals With Risk Factors Following the Fourth Dose of Severe Acute Respiratory Syndrome Coronavirus 2 BNT162b2 Vaccine","abstract":"To the Editor—We read with interest the article by Mwimanzi et al about humoral responses after second and third doses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA vaccination in older adults [1]. Here, we determined the effects of consecutive 4 BNT162b2 doses on neutralizing activity in sera from participants aged ≥60 years and those with risk factors against SARS-CoV-2 Wuhan and 2 Omicron sublineages, and analyzed longitudinal changes of neutralization activity pre– and post–second through fourth BNT162b2 doses in a prospective study over 490 days. In the present prospective clinical study, 32 of 225 healthcare workers in Kumamoto General Hospital, Japan (225 were initially recruited in the primary clinical study [2]), who were either ≥60 years of age and/or had preexisting diseases/risk factors (see demographic characteristics in Supplementary Table 1A) were enrolled. These 32 participants received a fourth BNT162b2 dose as they had risk of developing severe coronavirus disease 2019. The SARS-CoV-2 neutralizing activity (50% neutralization titer [NT50]) of their sera against the Wuhan strain of SARS-CoV-2 was determined over 490 days using sera collected consecutively on (i) 1 week post–second dose, (ii) 2 weeks post–third dose, (iii) 1 week pre–fourth dose, and (iv) 2 weeks post–fourth dose (Supplementary Methods), representing a continuation of our previous studies [2–4]. We also evaluated the profile of S1-binding immunoglobulin G (IgG) levels following pre–/post–fourth dose (on days 300/490). In addition, we determined NT50 of the same sera using VeroE6TMPRSS cells against infectious Omicron BA.2 and BA.5 variant sublineages, whose emergence has been associated with the present explosive increases globally [5]. Against SARS-CoV-2 Wuhan, moderate neutralizing activity was seen on day 28, 1 week after second-dose samples (Figure 1A, mean NT50 = 307), whereas there was a remarkable rise in neutralizing activity of the same participants’ sera of 2 weeks after third-dose administration (day 300), achieving a mean NT50 of 2238 (Figure 1A). On day 470 (1 week pre–fourth dose), the mean NT50 decreased to 541, 24% of the peak value on day 300 (2 weeks post–third dose) (Figure 1A). However, by day 490, 2 weeks post–fourth dose, neutralization activity was restored to 2096 (Figure 1A). The mean S1-binding IgG levels in pre–/post–fourth dose sera also showed an increase, from 247 on day 470 (1 week pre–fourth dose) to 1152 on day 490 (2 weeks post–fourth dose) (Supplementary Table 1B). Neutralizing activity of post–second, third, and fourth dose sera against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Wuhan strain, Omicron BA.2, and Omicron BA.5. Temporal changes of neutralizing activity of participants’ sera over 490 days post–first dose are shown. BNT162b2 doses were administered on days 0, 21, 287, and 477. A, The 50% neutralization titers (NT50) of participants’ sera against infection by SARS-CoV-205–2N strain were determined on days 7, 28, 60, 90, 150, 280, 300, 360, 470, and 490 post–first dose using VeroE6TMPRSS2 cell-based neutralization assay. Solid circles denote NT50 titers of each participant's serum and filled bars denote average NT50 titers of 32 participants’ sera at each time point. Geometric mean NT50 titers and ranges of NT50 at each time point are shown at the bottom. B, Temporal changes of neutralizing activity of participants’ sera at day 28, 300, 470, and 490 post–first dose against Omicron BA.2 and BA.5 variants are shown. Solid circles denote NT50 titers of each participant's serum and filled bars denote average NT50 titers of 32 participants’ sera at each time point. The NT50 values were found to be normally distributed following conversion to the log10 values and the differences between day 300 and day 490 values were calculated using paired t test. On the other hand, mean NT50 values against BA.2 and BA.5 on day 28, 1 week post–second dose were only 27 and","journal":"The Journal of Infectious Diseases","year":2022,"id":277023,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.959,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":942792,"name":"Sachiko Otsu","orcid":null,"position":1,"is_corresponding":false},{"id":652363,"name":"Yasuko Ichikawa","orcid":null,"position":2,"is_corresponding":false},{"id":495658,"name":"Nobuyo Higashi‐Kuwata","orcid":"0000-0002-9404-3532","position":3,"is_corresponding":false},{"id":541184,"name":"Shuzo Matsushita","orcid":"0000-0002-9649-8821","position":4,"is_corresponding":false},{"id":651055,"name":"Shinya Shimada","orcid":"0000-0002-8719-0729","position":5,"is_corresponding":false},{"id":295833,"name":"Hiroaki Mitsuya","orcid":"0000-0001-9274-3853","position":6,"is_corresponding":false},{"id":651046,"name":"Masayuki Amano","orcid":"0000-0003-0516-9502","position":0,"is_corresponding":true}],"reference_count":5,"raw_metadata":null,"created_at":"2026-07-19T00:28:34.768552Z","pmid":"36134611","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}