Citation: Ngare, I.; Tan, T.S.; Toyoda, M.; Kuwata, T.; Takahama, S.; Nakashima, E.; Yamasaki, N.; Motozono, C.; Fujii, T.; Minami, R.; et al. Factors Associated with Neutralizing Antibody Responses following 2-Dose and 3rd Booster Monovalent COVID-19 Vaccination in Japanese People Living with HIV. Viruses 2024, 16, 555. https://doi.org/ 10.3390/v16040555 Academic Editor: Cynthia Derdeyn Received: 8 February 2024 Revised: 8 March 2024 Accepted: 25 March 2024 Published: 2 April 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). viruses Article Factors Associated with Neutralizing Antibody Responses following 2-Dose and 3rd Booster Monovalent COVID-19 Vaccination in Japanese People Living with HIV Isaac Ngare 1,2 , Toong Seng Tan 1 , Mako Toyoda 1 , Takeo Kuwata 1 , Soichiro Takahama 3 , Eriko Nakashima 3 , Naoya Yamasaki 4 , Chihiro Motozono 1 , Teruhisa Fujii 4 , Rumi Minami 3 , Godfrey Barabona 1 and Takamasa Ueno 1,2,5, * 1 Joint Research Center for Human Retrovirus Infection, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-8555, Japan; ngareisaac@yahoo.com (I.N.); tstan@mgh.harvard.edu (T.S.T.); makotoyo@kumamoto-u.ac.jp (M.T.); tkuwata@kumamoto-u.ac.jp (T.K.); motozono@kumamoto-u.ac.jp (C.M.); barabona@kumamoto-u.ac.jp (G.B.) 2 Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan 3 NHO, Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-ku, Fukuoka 810-8563, Japan; takahama.soichiro.bt@mail.hosp.go.jp (S.T.); nakashima.eriko.rj@mail.hosp.go.jp (E.N.); minami.rumi.ad@mail.hosp.go.jp (R.M.) 4 Division of Transfusion Medicine, Hiroshima University Hospital, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8551, Japan; naoya64@hiroshima-u.ac.jp (N.Y.); teruchan@hiroshima-u.ac.jp (T.F.) 5 Joint Research Center for Human Retrovirus Infection, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima 890-8544, Japan * Correspondence: uenotaka@kumamoto-u.ac.jp Abstract: People living with HIV (PLWH) could be at risk of blunted immune responses to COVID-19 vaccination. We investigated factors associated with neutralizing antibody (NAb) responses against SARS-CoV-2 and variants of concern (VOCs), following two-dose and third booster monovalent COVID-19 mRNA vaccination in Japanese PLWH. NAb titers were assessed in polyclonal IgG fractions by lentiviral-based pseudovirus assays. Overall, NAb titers against Wuhan, following two- dose vaccination, were assessed in 82 PLWH on treatment, whereby 17/82 (20.73%) were classified as low-NAb participants. Within the low-NAb participants, the third booster vaccination enhanced NAb titers against Wuhan and VOCs, albeit to a significantly lower magnitude than the rest. In the multivariate analysis, NAb titers against Wuhan after two-dose vaccination correlated with age and days since vaccination, but not with CD4 + count, CD4 + /CD8 + ratio, and plasma high-sensitivity C-Reactive protein (hsCRP). Interestingly, an extended analysis within age subgroups revealed NAb titers to correlate positively with the CD4 + count and negatively with plasma hsCRP in younger, but not older, participants. In conclusion, a third booster vaccination substantially enhances NAb titers, but the benefit may be suboptimal in subpopulations of PLWH exhibiting low titers at baseline. Considering clinical and immune parameters could provide a nuanced understanding of factors associated with vaccine responses in PLWH. Keywords: SARS-CoV-2; neutralizing antibodies; COVID-19 vaccination; HIV; variants of concern 1. Introduction The rollout of global COVID-19 vaccination raised concerns over the ability of people living with HIV (PLWH) to elicit optimal immune responses given their underrepresen- tation in preceding clinical trials [1,2]. A growing body of literature now suggests that although PLWH on antiretroviral therapy (ART) can mount antibody responses at a compa- rable magnitude to non-HIV-infected individuals [3,4], certain subpopulations of PLWH, such as those with suboptimal CD4 + count recovery, have shown attenuated antibody Viruses 2024, 16, 555. https://doi.org/10.3390/v16040555 https://www.mdpi.com/journal/viruses