Aaron A.R. Tobian’s research while affiliated with Johns Hopkins University and other places

Solid organ transplant recipients (SOTRs) suffer more frequent and more severe infections due to their compromised immune responses resulting from immunosuppressive treatments designed to prevent organ rejection. Pharmacological immunosuppression can adversely affect immune responses to vaccination. A cohort of kidney transplant recipients (KTRs) received their third dose of ancestral, monovalent COVID-19 vaccine in the context of a clinical trial and antibody responses to the vaccine strain, as well as two Omicron variants BA.1 and BA.5 were investigated and compared with healthy controls who also received a third dose of mRNA vaccine (HCs). Total IgG and live virus neutralizing antibody titers were reduced in KTRs compared with controls for all variants. KTRs displayed altered IgG subclass switching, with significantly lower IgG3 antibodies. Responses in KTRs were also very heterogeneous, with some individuals showing strong responses but a significant number showing no Omicron-specific neutralizing antibodies. Taken together, immune responses after COVID-19 vaccination in KTRs were not only lower than HCs but highly variable, indicating that simply increasing the number of vaccine doses alone may not be sufficient to provide greater protection in this population. These findings underscore the need for tailored vaccination strategies for immunosuppressed populations, such as KTRs. Alternative formulations and doses of COVID-19 vaccines should be considered for people with severely compromised immune systems, as more frequent vaccinations may not significantly improve the response, especially regarding neutralizing antibodies. IMPORTANCE This study addresses the challenges faced by kidney transplant recipients (KTRs) in mounting effective immune responses against COVID-19. By evaluating the antibody responses to a third dose of monovalent mRNA COVID-19 vaccine and its effectiveness against Omicron subvariants (BA.1 and BA.5), this study reveals significant reductions in both binding and neutralizing antibodies in KTRs compared with healthy controls. The research highlights altered IgG subclass switching and heterogeneous responses within the KTR population. Reduced recognition of variants, coupled with differences in IgG subclasses, decreases both the quality and quantity of protective antibodies after vaccination in KTRs. These findings underscore the need for tailored vaccination strategies for immunosuppressed populations, such as KTRs. Alternative formulations and doses of COVID-19 vaccines should be considered for people with severely compromised immune systems, as more frequent vaccinations may not significantly improve the response, especially regarding neutralizing antibodies.

Background Genital inflammation increases HIV susceptibility and is associated with the density of pro-inflammatory anaerobes in the vagina and coronal sulcus. The penile urethra is a critical site of HIV acquisition, although correlates of urethral HIV acquisition are largely unknown. While Streptococcus mitis is a consistent component of the urethral flora, the presence of Gardnerella vaginalis has been linked with prior penile-vaginal sex and urethral inflammation. Here, we use a flow cytometry-based bacterial assay to quantify urethral IgA and IgG that bind G. vaginalis and S. mitis in a cross-sectional cohort of 45 uncircumcised Ugandan men and to evaluate their association with the urethral microbiome and local soluble immune factors. Results Urethral antibodies binding both bacterial species were readily detectable, with G. vaginalis predominantly bound by IgA, and S. mitis equivalently by IgA and IgG. Gardnerella vaginalis-binding IgA was elevated in participants with detectable urethral Gardnerella, with the latter only present in participants who reported prior penile-vaginal sex. In contrast, detectable urethral S. mitis was not associated with sexual history or levels of S. mitis-binding IgA/IgG. The time from the last penile-vaginal sex was inversely correlated with the urethral concentrations of total IgA, G. vaginalis-binding IgA, and chemokines IL-8 and MIP-1β; these inflammatory chemokines were independently associated with higher total IgA concentration, but not with G. vaginalis-binding IgA. Conclusions This first description of microbe-binding antibodies in the penile urethra suggests that urethral colonization by Gardnerella after penile-vaginal sex specifically induces a G. vaginalis-binding IgA response. Prospective studies of the host-microbe relationship in the urethra may have implications for the development of vaccines against sexually-transmitted bacteria. EnGLria5fUgKACmpttUN3NVideo Abstract

Background RSV causes serious morbidity in solid organ transplant recipients (SOTRs). Novel RSV vaccines are highly protective in the general population, yet immunogenicity among SOTRs is unknown. Demographic and Transplant Characteristics of SOTRs Reporting RSV Vaccination Methods Within a national, prospective cohort study SOTRs submitted whole blood samples at baseline and 2, 4, and 12 weeks post receipt of RSV vaccination (RSVPreF3 [GSK, AREXVY™] or RSVpreF [Pfizer, ABRYSVO™]) between October 2023-March 2024. Plasma prefusion F IgG and IgM (preF Ab) was tested using the Meso Scale Discovery platform and compared between baseline and 4 weeks to assess fold-change (FC); the proportion achieving high-titer Ab (IgG ≥high-titer reference plasma [BEI Resources]) at 4 weeks was also assessed. Ab measures were compared between GSK and Pfizer vaccinees. Change in Prefusion F IgG Titers following RSV Vaccination in SOTRs Blue dots represent Pfizer vaccine recipients and pink dots represent GSK vaccine recipients. Individual titer trajectories are connected by grey lines. High-titer response is denoted by the upper red horizontal line, corresponding to high-titer pooled control plasma. Results Among 27 participants (median [IQR] age 65-73 years, 44% female, 59% GSK and 30% Pfizer vaccinees [11% unspecified]), median [IQR] preF IgG rose from 76,252 [59,116-185,845] to 424,618 [153,503-1,905,705] AU/mL by 4 weeks (median [IQR] FC 5.54 [2.06-13.26]). Overall, 67% demonstrated IgG FC ≥4 at 4 weeks (69% GSK vs 50% Pfizer vaccinees) and 52% demonstrated high-titer Ab at 4 week (62% GSK vs 25% Pfizer vaccinees); clinical and transplant factors were similar between response groups. By 12 weeks, 56% showed high-titer Ab (62% GSK vs 38% Pfizer vaccinees) (Figure). Response patterns varied, including greater IgM change from baseline to 4 weeks in GSK vaccinees (IgM FC ≥4: 31% GSK vs 25% Pfizer) and more pronounced IgG peak-and-wane in GSK vaccinees (median FC from 4 to 12 weeks 1.01 GSK vs 0.49 Pfizer). No participants reported RSV infection during follow up. Prefusion F IgG Titers pre and post RSV Vaccination in SOTRs, by Vaccine Type Blue dots represent Pfizer vaccine recipients and pink dots represent GSK vaccine recipients. High-titer response is denoted by the upper red horizontal line, corresponding to high-titer pooled control plasma. Open circles represent ≥ 4-fold change in titer at 4 weeks. Conclusion RSV preF Ab responses are highly variable and often attenuated in SOTRs following RSV vaccination; 44% did not show high-titer Ab at 4 weeks. Response level and pattern vary by vaccine platform (i.e., adjuvanted versus unadjuvanted), which may imply different risk periods post vaccination and potential role for additional vaccine doses to improve immunoprotection. Prefusion F IgM Titers pre and post RSV Vaccination in SOTRs, by Vaccine Type Blue dots represent Pfizer vaccine recipients and pink dots represent GSK vaccine recipients. Open circles represent ≥ 4-fold change in titer at 4 weeks. Disclosures Andrew H. Karaba, MD PhD, Hologic: Advisor/Consultant William Werbel, MD, AstraZeneca: Advisor/Consultant|AstraZeneca: Honoraria|IDSA: Advisor/Consultant|Novavax: Advisor/Consultant

Background The Association for the Advancement of Blood and Biotherapies guidelines recommend the use of high‐titer COVID‐19 convalescent plasma (CCP) for patients with SARS‐CoV‐2 at high risk of disease progression, including those who are immunocompromised. We hypothesized that conventional plasma units have comparable neutralizing antibody levels to CCP. Study Design and Methods Conventional plasma and CCP units were obtained from blood suppliers. Quantitatively measured antibodies to SARS‐CoV‐2 were assessed using the MesoScale Discovery multiplex electrochemiluminescence immunoassay. Binding antibody distributions were compared with Wilcoxon rank‐sum tests. SARS‐CoV‐2 neutralizing antibodies were analyzed using the GeneScript ELISA‐based neutralization assay. The proportion of conventional and CCP units with a percent signal inhibition of ≥80% (as defined by the United States Food and Drug Administration for CCP in 2021) and exact binomial confidence intervals (CIs) were calculated. Results Among 218 conventional plasma units and 74 CCP units collected between September 2023 and July 2024, the distribution of total antibody binding levels largely overlapped between conventional plasma and CCP, though statistically significant differences in median nucleocapsid and spike Omicron variant concentrations were observed. Median percent signal neutralization was 97.5% (range 3.4%–98.6%) among conventional plasma units and 97.7% (range 95.4%–98.6%) among CCP units. For conventional plasma, 95.0% (95% CI = 91.2%–97.5%) met the neutralization antibody threshold for high‐titer CCP. For CCP, 100% (95% CI = 95.1%–100.0%) met the neutralization threshold for high‐titer CCP. Conclusion Conventional plasma units demonstrate similar median antibody concentration to CCP units. In countries or regions where licensed CCP is unavailable and titers are unknown, transfusion of multiple conventional plasma units may be of clinical utility.