Prediction of the progression of an infectious disease outbreak is important for planning and coordinating a response. Differential equations are often used to model an epidemic outbreak's behaviour but are challenging to parameterise. Furthermore, these models can suffer from misspecification, which biases predictions and parameter estimates. Stochastic models can help with misspecification but are even more expensive to simulate and perform inference with. Here, we develop an explicitly likelihood-based variation of the generalised profiling method as a tool for prediction and inference under model misspecification. Our approach allows us to carry out identifiability analysis and uncertainty quantification using profile likelihood-based methods without the need for marginalisation. We provide justification for this approach by introducing a new interpretation of the model approximation component as a stochastic constraint. This preserves the rationale for using profiling rather than integration to remove nuisance parameters while also providing a link back to stochastic models. We applied an initial version of this method during an outbreak of measles in Samoa in 2019–2020 and found that it achieved relatively fast, accurate predictions. Here we present the most recent version of our method and its application to this measles outbreak, along with additional validation.

BACKGROUND:The COVID-19 pandemic has greatly affected nursing home residents (NHRs), a vulnerable group with high rates of illness and death. While vaccination is essential for reducing infections and severe outcomes in the short term, it is important to understand how long antibody levels and neutralizing activity last. This understanding will help us create effective public health strategies for the long term. According to current CDC guidelines, individuals over 65 should receive a booster dose six months after their previous vaccination. METHODS:This observational retrospective cohort study analyzed post-vaccination serum from samples with up to 400 days of follow-up from 697 NHRs and 127 healthcare workers (HCWs) across Northeast Ohio and Rhode Island. Analyses were conducted to model decay rates of neutralizing and binding antibody titers and the impact of previous exposures to SARS-CoV-2 on these decay rates. RESULTS:Results indicate that NHRs show Wuhan and Omicron BA.4/5 neutralizing and binding antibody titers diminish significantly from 2 weeks to 12 months post-vaccination. NHRs with prior infection show higher peak antibody titers and slower decay than those naive to infection. Antibody levels after vaccination for infection-naive NHR lagged HCW and NHR with prior infection, but then decayed at a similar rate. CONCLUSION:The immunologic findings in this cohort of NHR align with the existing real-world clinical effectiveness data in older individuals and support the CDC recommendation of a bi-annual vaccination to reduce severe COVID-19 outcomes in persons age 65 and older.

Objectives:To evaluate feasibility of establishing syndromic respiratory virus surveillance in a network of U.S. nursing homes, using CLIA-waived point-of-care (POC) molecular PCR testing, with centrally delivered results. Design:Single-arm feasibility pilot study. Setting and Participants:Twenty-three nursing homes (NHs) in six U.S. states, representing approximately 2,500 residents. Methods:A CLIA-waived POC molecular PCR testing device was implemented for on-site testing of respiratory syncytial virus (RSV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and influenza A and B from collected nasal swabs. Symptom data was entered at the time of testing. Test results were transmitted to a centralized, web-based dashboard providing near real-time surveillance from November 2023 to January 2025. Surveys of NH staff assessed device usability, workflow integration, impact on testing procedures, and infection and outbreak awareness. Results:The established syndromic respiratory virus surveillance network conducted 1,745 point-of-care tests between November 2023 and January 2025, identifying 360 infections, including 160 COVID-19, 115 influenza A and B, and 81 RSV infections. Symptom data was captured for 99.5% of tests. Implementation was associated with high data completeness and integration into facility testing workflows. Staff reported an impact on testing protocols, infection awareness, and time to diagnosis. Conclusions:Implementation of a CLIA-waived POC molecular testing device with centralized reporting was feasible across a geographically diverse NH network. The system achieved high data capture, identified substantial viral activity, and demonstrated value for clinical management using real-time diagnostic results. This approach can be adapted for local, regional, or national real-time reporting or future pragmatic interventional studies.

Institutionalized and community-dwelling older adults have been greatly impacted by the COVID-19 pandemic with increased morbidity and mortality. The advent of vaccines and their widespread use in this population has brought about a dramatic turnaround in COVID-19 outcomes. The immunogenicity and effectiveness of the various vaccine options worldwide will be discussed. Optimizing vaccine usage will remain crucial to maximize protection due to reduced initial immunity, the emergence of variant strains, and the waning of immunity over time. There are also lessons learned specific to older populations for future pandemics of novel pathogens where there is minimal to no prior immunity.

OBJECTIVES:Nursing home residents received updated monovalent SARS-CoV-2 vaccines to protect them from the most recently emerging SARS-CoV-2 variants. We evaluated nursing home residents for the extent and durability of protection from hospitalization or death after monovalent KP.2 vaccination. DESIGN:Retrospective cohort study using a target trial emulation design. We conducted a sequential, daily comparison of those who did and did not receive a KP.2 vaccination during the study period. Residents who received KP.2 were matched to unvaccinated residents based on index date and propensity scores incorporating demographics, vaccination status, and basic clinical characteristics. SETTING AND PARTICIPANTS:Long-stay residents living in Veterans Affairs nursing homes between September 18, 2024, and October 30, 2024. METHODS:The primary exposure was KP.2 vaccination vs no SARS-CoV-2 vaccine during the study period. The primary outcome was a test-confirmed SARS-CoV-2 infection. Secondary outcome was composite outcome of COVID-19-associated hospitalizations within 21 days or death within 30 days of confirmed infection. RESULTS:Among eligible residents, a matched cohort of 1711 paired person trials were created (average age 76, 95% male, 28% African American). Vaccine effectiveness against COVID-19 infection was 38% at week 12 (95% CI, 13%-56%) and 4% at week 18 (95% CI, -30 to 29%). Vaccine effectiveness against hospitalization or death was 77% at week 12 (95% CI, 60%-90%) and 53% at week 18 (95% CI, 21%-71%). CONCLUSION AND IMPLICATIONS:Vaccination with the KP.2 updated SARS-CoV-2 vaccine provided significant clinical protection against hospitalization or death among nursing home residents. This protection started to wane within a few months of vaccination, mirroring antibody decline reported in other studies. Our findings support consideration of twice-annual vaccination strategy to optimize protection in this vulnerable population.

Nursing home residents (NHRs) remain among the most vulnerable to severe outcomes from SARS-CoV-2 infection. While mRNA-1273 (Spikevax, Moderna) and BNT162b2 (Comirnaty, Pfizer-BioNTech) vaccines are widely used in this population, comparative data on their immunogenicity, particularly after bivalent boosters, remain limited. We conducted a longitudinal immunologic evaluation of U.S. NHRs who received either the mRNA-1273 or BNT162b2 bivalent vaccine. Serum samples were collected 10-30 d post-vaccination. Anti-spike IgG levels were measured using a Luminex bead-based assay, and neutralizing titers were assessed via pseudovirus neutralization. Comparative analyses of the titer distributions were performed using two-sided Wilcoxon rank-sum tests. Both vaccine groups demonstrated strong humoral responses to the ancestral Wuhan strain and Omicron BA.4/5 subvariants. Spike-binding antibody levels and neutralization titers were comparable between the mRNA -1273 and BNT162b2 vaccine formulations. Conclusions: Both mRNA-1273 and BNT162b2 mRNA vaccines elicit similarly robust humoral immunity in NHRs, supporting their interchangeable use in booster strategies. Our findings underscore the importance of timely booster administration over exact product selection in protecting this high-risk, immunosenescent population.

The immune response to COVID-19 vaccines is diminished in older individuals. To understand the underlying immunobiology, we analyzed single-cell RNA-seq data from PBMCs of SARS-CoV-2 naive nursing home residents with varying humoral responses following BNT162b2 vaccination and validated via flow cytometry. Responders (R) (>4500 AU/mL anti-spike titers) showed enrichment for naive B cell (IGHD, BACH2, CD22) and naive CD4 T cell and early T follicular helper (Tfh)-related genes (CCR7, TCF7, LEF1, IL6ST, and TGFBR2). Non-responders (NR) (<20 AU/mL) displayed elevated markers of T cell senescence (KLRG1, CCL4, CCL5, and IL32), immune exhaustion (PD-1), and inflammation (TNF-α, IFN-γ). Flow cytometry revealed reduced CD4 T and B cell frequencies but higher CD8 T and NK cells in NR. Despite reduced B cell frequency, NR upregulated plasma B cell genes (PRDM1, XPB1, IRF4), suggesting dysregulated B cell differentiation. Our findings point to impaired lymphocyte responses and increased immunosenescence in NR, emphasizing the need for enhanced vaccine strategies in aging populations.

Objectives This study compares enhanced influenza vaccines recommended for older adults, adjuvanted flu vaccine (aTIV, FLUAD) vs high-dose flu vaccine (HD-IIV3, FLUZONE HD) to determine if they met noninferiority standards for older long-term care facility (LTCF) residents. Design A phase 4, randomized, active-controlled, noninferiority trial on influenza vaccine immunogenicity conducted over 2 influenza seasons (2018-2019 and 2019-2020) (NCT03694808). Setting and Participants Residents of LTCFs aged ≥65 years. Methods Participants were randomized 1:1 to receive either aTIV or HD-IIV3 using computer-generated randomization. Only laboratory personnel were blinded. Hemagglutination inhibition (HAI) and neuraminidase inhibition (NI) assays measured antibody responses at baseline and 28 days postvaccination. The primary outcome compared the geometric mean titers (GMTs) at day 28. Secondary outcomes included seroconversion rates and NI titers. Results We randomized 387 LTCF residents to receive either aTIV (n = 194) or HD-IIV3 (n = 193) over 2 flu seasons. We observed noninferior HAI levels at postvaccination day 28 to A/H1N1 and A/H3N2 for aTIV and HD-IIV3 (GMT ratio, 1.03; 95% CI, 0.76-1.4; and GMT ratio, 1.04; 95% CI, 0.73-1.48, respectively), meeting noninferiority criteria with 95% CI upper bounds <1.5. However, noninferiority criteria were not met for influenza B HAI levels (GMT ratio, 1.21; 95% CI, 0.91-1.61). Also, noninferiority criteria for HAI seroconversion were not met for any of the 3 strains. Applying the same noninferiority criteria to NI, both day 28 titer and seroconversion in aTIV were noninferior to HD-IIV3 for A/H1N1 and A/H3N2 strains. Conclusions and Implications Overall the anti-hemagglutinin and anti-neuraminidase titers demonstrate similarities between the vaccines and support them both being in the enhanced flu vaccine category preferentially recommended by the Centers for Disease Control and Prevention for people aged ≥65 years.

ImportanceInfluenza vaccination remains the most important intervention to prevent influenza morbidity and mortality among nursing home residents. The additional effectiveness of recombinant influenza vaccine vs standard dose vaccines was demonstrated in outpatient older adults but has not been evaluated in nursing home populations.ObjectiveTo compare hospitalization rates among residents in nursing homes immunized with a recombinant vs a standard dose egg-based influenza vaccine.Design, Setting, and ParticipantsThis pragmatic cluster randomized trial assessed nursing home residents 65 years or older residing in a US facility for 100 or more days before the start of influenza season (October 1). The study was conducted across the 2019 to 2020 and 2020 to 2021 influenza seasons and randomly assigned nursing homes 1:1 within blocks categorized by proportion of Black residents and prior resident hospitalization rates. Medicare claims data were used to evaluate resident-level hospitalization outcomes. Enrollment and allocation to treatment groups began on July 20, 2019. Data analysis began on January 1, 2021, with primary end points finalized June 30, 2024.InterventionNursing homes were cluster randomized to vaccinate all residents with recombinant quadrivalent influenza vaccine (RIV4) or standard egg-based quadrivalent inactivated influenza vaccine (IIV4).Main Outcome and MeasuresThe primary outcome was respiratory-related hospitalization. Secondary outcomes included death and hospitalization due to any cause.ResultsA total of 144 565 person observations (mean [SD] age, 77.4 [13.1] years; 63.0% female) at 1078 nursing homes were included, with 72 005 residents in nursing homes randomized to provide RIV4 and 72 560 residents in nursing home randomized to provide IIV4. In total, 85.6% of the residents received influenza vaccination. Baseline resident characteristics were comparable across treatment groups. For the primary end point of respiratory-related hospitalizations, there were 1387 hospitalizations (1.9%) in the RIV4 group vs 1424 (2.0%) in the IIV4 group (hazard ratio, 1.01; 95% CI, 0.62-2.17). Hospitalization rates by vaccine were similar for other hospitalization outcomes and death, overall, and by season and subgroups (gender, race, and comorbidities).Conclusions and RelevanceIn this cluster randomized trial of nursing homes, there was no significant difference between recombinant or standard dose vaccine for reducing hospitalizations associated with influenza illness. However, the COVID-19 pandemic restricting influenza activity along with poor vaccine match to circulating strains substantially limits the conclusions.Trial RegistrationClinicaltrials.gov Identifier: NCT03965195

BACKGROUND:Data suggest that antibody responses following COVID-19 vaccines are a correlate of protection. Some studies, including the clinical trials of COVID-19 mRNA vaccines, did not stratify and evaluate whether antibody responses to COVID-19 vaccines differed between the sexes or with aging. This gap in research is particularly relevant for older populations such as nursing home residents (NHR). We hypothesized that sex differences in vaccine-induced antibody responses may intersect with age and be diminished among older adults residing in nursing homes. METHODS:We analyzed serum samples from 638 NHRs collected serially after the primary two-dose series and three subsequent booster doses of mRNA SARS-CoV-2 vaccinations. We analyzed anti-Spike IgG and neutralizing antibody titers to the Wuhan and Omicron BA.4/5 variant strains. Mixed-effects models predicting log-transformed titers were estimated to compare responses across vaccine doses, focusing on sex-differential responses. For detected post-dose sex differences, additional sample times were analyzed to assess the duration of the difference. RESULTS:Following the primary series, female NHRs with a prior history of SARS-CoV-2 infection had significantly higher Wuhan anti-Spike antibodies and neutralizing antibody titers than male NHRs with differences persisting up to nine months post-vaccination. Subsequent monovalent booster doses and a bivalent booster dose eliminated this disparity. We did not detect any differential response to the Omicron BA.4/5 variant. CONCLUSIONS:The blunting of sex differences in antibody response observed following the primary series by the 1st booster dose underscores the importance of booster vaccination in this population.

Rationale:The Centers for Disease Control and Prevention (CDC) nursing home (NH) viral surveillance network (NHSN) reports data from a minority of NHs nationally and lags the infection detection by at least two weeks. We piloted a pragmatic approach to improve respiratory virus detection in NHs using a Clinical Laboratory Improvement Amendment (CLIA)-waived point of care (POC) molecular assay, aimed to improve RSV underreporting.Methods:We provided the Cepheid GeneXpert Xpress POC device to typically-sized NHs (∼100 beds) to facilitate diagnosis of symptomatic respiratory infections (ARI) as clinically indicated. The CLIA-waived device uses nasal swabs like for antigen testing, reports results for CoVID, influenza and RSV from a single swab in 34 minutes both to the facility and the cloud in real time. We collected Cepheid data from 11/23-9/24, and monthly respiratory tract infection data directly from NH staff on influenza, RSV, SARS-CoV-2 as identified in residents and respiratory virus vaccination rates. Results:In the 20 participating NHs in five health services regions, the Cepheid device confirmed influenza, RSV, or SARS-CoV-2 in 23.7% of specimens. Of the 1093 samples run, 84 (7.7%) were influenza A, 4 (0.4%%) were influenza B, 108 (9.9%) were SARS-CoV-2, and 59 (5.4%) were RSV, 4 (0.4%) detected >1 virus, and 834 (76.3%) detected no virus. For influenza A and B, Cepheid (88 cases) and staff reporting (87 cases) a similar number of cases. However, for SARS-CoV-2 reporting, with staff reported 542 cases compared to Cepheid's 108, suggesting a shift from the 34-minute POC test to the more efficient rapid antigen test for systematic testing. NH staff reported far fewer RSV (n=17) than identified by Cepheid (n=59 ). Staff reported 2023/2024 respiratory seasons vaccination rates for influenza, SARS-CoV-2, and RSV, at 77%, 54%, and 8% respectively, and collectively at a substantially higher rate than the CDC's NHSN and our network's NHs without POC molecular testing capability. Conclusion:Use of a POC PCR device that expands respiratory virus detection capability increases RSV detection and respiratory virus awareness for NH staff. These data align with literature indicating that RSV is often under-recognized due to limited testing capabilities and awareness as a cause of respiratory illness. Our findings emphasize the importance of improving RSV reporting to enhance public health surveillance and response strategies including use of the RSV vaccines that have as yet low uptake despite ACIP's specific recommendation for this population.

Abstract Background Respiratory tract infections (RTI) cause high morbidity and mortality among nursing home (NH) residents, yet their etiology and frequency remain understudied. We implemented multiplex respiratory panel (MRP) testing to describe RTI epidemiology in NH residents to inform efforts to reduce respiratory virus transmission in NH. Figure 1 Flow diagram and multiplex respiratory panel testing results of SNF residents in NH-PHRN, February–April, 2024. Methods The Nursing Home Public Health Response Network (8 academic sites and 22 affiliated NHs) is conducting RTI surveillance with MRP testing. Staff collect nasal swab (NS) specimens and clinical data from symptomatic residents with suspected RTI. Specimens are collected within 72 hours of symptom onset and tested with the Roche ePlex Respiratory Pathogen Panel 2 (17 viral and bacterial pathogens, Figure 1) in a central laboratory. We describe MRP results, symptoms, and characteristics of residents tested during February–April 2024. We compared symptoms between NH residents with and without viral detection on MRP with Chi-Squared and Fisher Exact tests. Figure 2 Multiplex respiratory pathogen testing results among 81 enrolled residents in 19 nursing homes in NH-PHRN, February – April 2024, United States. *One resident tested positive for both Human Rhinovirus/Enterovirus and Coronavirus. **Influenza A subtype was H3 for all four specimens. Results Of 106 symptomatic residents with suspected RTI, 81 (72%) were tested (Figure 1). MRP detected ≥1 virus in 36/81 (44%) specimens; SARS-CoV-2 was the most common (14%), followed by seasonal coronavirus (12%) (Figure 2). Among residents tested, cough (78%), runny nose (43%), and sore throat (31%) were the most common symptoms. Sore throat was more common among residents with viral detection (53% vs. 13%; P=0.0001) (Figure 3). Of 75 tested residents with demographic and clinical data, median age was 80 (range 53–90), 59% were female, 19% were Black, 68% were long stay ( >100 days), and 99% had received a COVID-19 vaccine. Among 52 tested residents with treatment and outcome data, 14 (27%) received antibacterials, 11 (21%) were hospitalized, and 3 (6%) died. Of 25/52 residents with viral detection on MRP and complete treatment and outcome data, 4 (16%) received antibacterials, 6 (24%) were hospitalized (SARS-CoV-2 = 3, seasonal coronavirus = 2, Influenza A = 1) and none died. Figure 3 Frequency and percentage of symptoms and other clinical characteristics among 81 residents who underwent multiplex respiratory pathogen specimen collection in 19 nursing homes in NH-PHRN, February – April 2024, United States. We used Chi-Square and Fisher Exact tests to compare the type and frequency of symptoms among residents who had multiplex tests with and without pathogens detected. One asymptomatic resident who had no pathogen detected was tested due to leukocytosis. *Comparison P=0.04. **Comparison P=0.01. ***Comparison P=0.0001. Conclusion MRP testing identified a virus in almost half of tested NH residents with suspected RTI at the end of the viral respiratory season. Ongoing surveillance will help describe the burden and clinical relevance of viral respiratory pathogens in NH residents and identify areas of improvement for respiratory virus infection prevention. Disclosures Yasin Abul, MD, Moderna: Grant/Research Support|Moderna, Abt, CDC: Grant/Research Support David Canaday, MD, Moderna: Grant/Research Support|Pfizer: Grant/Research Support Jon P. Furuno, PhD, Merck & Co., Inc: Grant/Research Support Stefan Gravenstein, MD, MPH, CDC: Advisor/Consultant|CDC: Grant/Research Support|Genentech: Advisor/Consultant|Genentech: Grant/Research Support|Genentech: Honoraria|GlaxoSmithKline: Advisor/Consultant|GlaxoSmithKline: Grant/Research Support|GlaxoSmithKline: Honoraria|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Janssen: Honoraria|Moderna: Advisor/Consultant|Moderna: Grant/Research Support|Moderna: Honoraria|NIH: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Sanofi: Advisor/Consultant|Sanofi: Grant/Research Support|Sanofi: Honoraria|Seqirus: Advisor/Consultant Lona Mody, MD, MS, Nanovibronix: Grant/Research Support Morgan Katz, MD, MHS, Ageless Innovation: Advisor/Consultant

Importance Influenza vaccination remains the most important intervention to prevent influenza morbidity and mortality among nursing home residents. The additional effectiveness of recombinant influenza vaccine vs standard dose vaccines was demonstrated in outpatient older adults but has not been evaluated in nursing home populations. Objective To compare hospitalization rates among residents in nursing homes immunized with a recombinant vs a standard dose egg-based influenza vaccine. Design, Setting, and Participants This pragmatic cluster randomized trial assessed nursing home residents 65 years or older residing in a US facility for 100 or more days before the start of influenza season (October 1). The study was conducted across the 2019 to 2020 and 2020 to 2021 influenza seasons and randomly assigned nursing homes 1:1 within blocks categorized by proportion of Black residents and prior resident hospitalization rates. Medicare claims data were used to evaluate resident-level hospitalization outcomes. Enrollment and allocation to treatment groups began on July 20, 2019. Data analysis began on January 1, 2021, with primary end points finalized June 30, 2024. Intervention Nursing homes were cluster randomized to vaccinate all residents with recombinant quadrivalent influenza vaccine (RIV4) or standard egg-based quadrivalent inactivated influenza vaccine (IIV4). Main Outcome and Measures The primary outcome was respiratory-related hospitalization. Secondary outcomes included death and hospitalization due to any cause. Results A total of 144 565 person observations (mean [SD] age, 77.4 [13.1] years; 63.0% female) at 1078 nursing homes were included, with 72 005 residents in nursing homes randomized to provide RIV4 and 72 560 residents in nursing home randomized to provide IIV4. In total, 85.6% of the residents received influenza vaccination. Baseline resident characteristics were comparable across treatment groups. For the primary end point of respiratory-related hospitalizations, there were 1387 hospitalizations (1.9%) in the RIV4 group vs 1424 (2.0%) in the IIV4 group (hazard ratio, 1.01; 95% CI, 0.62-2.17). Hospitalization rates by vaccine were similar for other hospitalization outcomes and death, overall, and by season and subgroups (gender, race, and comorbidities). Conclusions and Relevance In this cluster randomized trial of nursing homes, there was no significant difference between recombinant or standard dose vaccine for reducing hospitalizations associated with influenza illness. However, the COVID-19 pandemic restricting influenza activity along with poor vaccine match to circulating strains substantially limits the conclusions. Trial Registration Clinicaltrials.gov Identifier: NCT03965195

Abstract Background Immune response and memory changes with aging and disease, features that may be amplified in long-term care populations. We evaluated the kinetics of immunity following vaccination and infection in nursing home residents (NHR). Methods In a cohort of NHR with continuous enrollment since 2020, we drew blood before and after mRNA COVID-19 vaccines and SARS-COV-2 infection. We identified prior and breakthrough infections and the intervals between vaccinations and samples to describe decay kinetics of neutralizing titers over time. Assuming a peak response occurring 14 days after each dose, we estimated mixed-effects exponential decay models, stratified by dose and prior infection and assuming a random intercept for each subject. From these models, we estimated peak value and rates of decay for Wuhan and Omicron BA.4/5 neutralizing titers. Results Our analysis cohort followed 412 NHR (median (IQR) age = 76 (69, 86); 49% female). Among infection-naive NHR, the estimated Wuhan rate of decay did not differ significantly across doses. Prior infected NHR showed significantly longer half-lives after all booster doses than with the primary series (Figure 1, Table 1). Decay models of Omicron BA.4/5 neutralizing titers following booster doses showed significant increases in peak titer for each subsequent booster among both the naive and prior infection subgroups. The decay rates increased significantly over the first monovalent booster, but no differences in rates were detected between infection-naive and prior infection subgroups (Figure 2). The estimated half-lives across strain, dose, and infection subgroups ranged from roughly 50 to 150 days; the differences in peak and decay are reflected in the predicted titers at 6 and 12 months after vaccination (Table 2). Conclusion Following primary series and booster doses, NHR with prior infection enjoy both higher peaks and a similar or slower decline in neutralizing titers than naive NHR, demonstrating the benefits of hybrid immunity with subsequent vaccinations. Neutralizing titers decline sufficiently fast to warrant updating vaccines before the prior dose anniversary. Understanding the kinetics of serial doses within this population can assist in vaccine planning and priorities among NHR. Disclosures Yasin Abul, MD, Moderna: Grant/Research Support|Moderna, Abt, CDC: Grant/Research Support Alejandro Balazs, PhD, Cure Systems LLC: Ownership Interest Stefan Gravenstein, MD, MPH, CDC: Advisor/Consultant|CDC: Grant/Research Support|Genentech: Advisor/Consultant|Genentech: Grant/Research Support|Genentech: Honoraria|GlaxoSmithKline: Advisor/Consultant|GlaxoSmithKline: Grant/Research Support|GlaxoSmithKline: Honoraria|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Janssen: Honoraria|Moderna: Advisor/Consultant|Moderna: Grant/Research Support|Moderna: Honoraria|NIH: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Sanofi: Advisor/Consultant|Sanofi: Grant/Research Support|Sanofi: Honoraria|Seqirus: Advisor/Consultant David Canaday, MD, Moderna: Grant/Research Support|Pfizer: Grant/Research Support

Studies have demonstrated that repeated mRNA vaccination enhances the breadth of neutralization against diverse severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. However, the development of antibodies capable of neutralizing across the Coronavirinae subfamily is poorly understood. In this study, we analyze serum samples to determine their neutralization breadth and potency and identify their antigenic targets. Using a cohort of older individuals and healthcare workers, we track correlates of broad neutralizing responses, including fusion peptide (FP) antibody elicitation. We find that although broadly neutralizing responses are often a result of receptor-binding domain (RBD)-specific antibodies, a rare subset of donors produce FP-specific broadly neutralizing responses. Interestingly, FP-specific antibodies are not observed in COVID-naive individuals, irrespective of vaccination regimen; rather, they occur following natural infection or vaccine breakthrough. This study highlights which epitope targets underpin broadly neutralizing antibody responses to coronaviruses and suggests that existing vaccines are insufficient to promote the elicitation of FP-directed broadly neutralizing coronavirus antibodies.

BACKGROUND:Nursing homes (NHs) were disproportionately affected by the COVID-19 pandemic. However, little is known regarding the kinetics of SARS-CoV-2 shedding in NH residents and staff, which could inform treatment and infection prevention. METHODS:We enrolled NH residents and staff in eight US states from April to November 2023 and analyzed the kinetics of SARS-CoV-2 using serial antigen and molecular (RT-PCR) tests, whole genome sequencing, and viral culture (VC). Symptoms, vaccination, and treatment were collected via interviews and chart review. Viral load trajectories were modeled with gamma distribution functional forms. Antigen and VC test positivity over time were assessed using a Chi-squared test. RESULTS:Of the 587 enrolled participants, 86 tested positive and 73 underwent testing for ≥ 10 days; most residents (78%) and staff (87%) had ≥ 3 COVID-19 vaccine doses. The modeled SARS-CoV-2 proliferation period (period prior to reaching peak viral load) had ended for 48% (14/29) of residents and 56% (9/16) of staff when they took the initial RT-PCR test. Both antigen and VC showed higher positivity rates early in the course of disease (Days 0-5 vs. Days ≥ 6) (antigen: p < 0·001, VC: p < 0·001). VC positivity was 15% after Day 5 (14/96); two participants were VC positive after Day 10. CONCLUSIONS:Peak viral load occurs early in the disease, suggesting asymptomatic and presymptomatic transmission may be a significant driver of transmission. Only two participants had a positive VC after Day 10, supporting current isolation and return to work recommendations.

Tuberculosis (TB) remains a worldwide public health threat, in part because of the limited efficacy of current BCG vaccination. Respiratory infection with Mycobacterium tuberculosis (Mtb) is most often followed by the development of protective immunity that contains the pathogen, resulting in latent tuberculosis infection (LTBI). We previously introduced bronchoscopic challenge of LTBI individuals using instillation of purified protein derivative (PPD) of Mtb to model specific induced local recall responses in the human lung. Here, we examined phenotypic and functional aspects of human airway CD4+ T cell populations in LTBI that correlate with protection from Mtb in animal infection models. Baseline bronchoalveolar lavage (BAL) was enriched for CD4+ T cells expressing the KLRG−/CD69+ tissue resident-memory (TRM) phenotype. Both Th1 (CCR6−CCR4−CXCR3+) and Th1* (CCR6+CCR4−CXCR3+) CD4+ T cell subsets demonstrated polyfunctional IFN-γ+TNF-α+ cytokine responses in response to in vitro PPD stimulation. Bronchoscopic PPD challenge, although leading to less robust cellular recruitment than observed previously, preserved the predominance of KLRG1−CD69+ TRM and also of CD4+ T cells that displayed IFN-γ+TNF-α+ dual cytokine production in response to PPD. CD4+ T cells of both control and PPD challenged human lung segments displayed increased expression of the protective CD153 molecule; CD153 expression also correlated with increased cytokine polyfunctionality, particularly of polyfunctional IFN-γ+IL-2+TNF-α+ and IFN-γ+TNF-α+ dual-positive cells. These results support the utility of BAL studies in LTBI to model human correlates of protection from Mtb with potential applicability to the design and initial evaluation of novel approaches to TB vaccination.

BACKGROUND:Nursing home residents (NHRs) remain at high risk for severe outcomes following SARS-CoV-2 infection. Omicron descendants have dominated circulating strains, with XBB in 2023 and KP.2 strain by mid-2024, leading to immune escape and increased transmissibility. We aimed to assess the immunogenicity of one versus two prior doses of the XBB.1.5 vaccines and potential differences in the subsequent response to the KP.2 booster. METHODS:We conducted a longitudinal immunologic evaluation of 131 NHRs in Ohio and Rhode Island. Samples were collected 2-6 weeks after the first and second XBB.1.5 vaccination doses, 60 days before KP.2 vaccination, and 2-6 weeks after the KP.2 booster. We measured anti-spike and neutralizing antibody titers to both XBB.1.5 and KP.2. RESULTS:NHRs who received two booster doses of the XBB.1.5 vaccine developed higher peak anti-spike antibody levels (29,777 AU/mL) and neutralizing titers (7082) compared to those with only one dose (13,788 AU/mL and 1293, respectively). Over time, anti-spike antibody and neutralizing titers declined, but both remained higher in the two-dose group before receiving the KP.2 vaccine. After vaccination with XBB.1.5, neutralization against KP.2 was significantly lower than against XBB.1.5, suggesting reduced cross-reactivity and highlighting the potential for immune escape. However, KP.2 vaccination markedly boosted neutralizing titers in all participants, regardless of their prior XBB.1.5 dose history. CONCLUSION:NHRs who received a two-dose regimen of the XBB.1.5 vaccine demonstrated stronger immune responses and higher pre-KP.2 titers than those who received a single dose. However, the diminished cross-protective neutralization of KP.2 highlights the variant's immune evasiveness. The KP.2 booster effectively elicited anti-KP.2 levels, supporting the continued use of updated, variant-matched boosters to protect high-risk populations such as NHRs.

Background Vaccines and vaccine boosting have blunted excess morbidity and mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in older nursing home residents (NHR). However, the impact of repeated vaccination on the T-cell response based on biological sex and prior infection of NHR remain understudied.Methods We examined T-cell responses to SARS-CoV-2 mRNA vaccines in a cohort of NHR and healthcare workers (HCW) over 2 years. We used interferon-gamma ELIspot and flow cytometry to assess T-cell response before, 2 weeks, and 6 months after the initial series and each of 2 booster vaccines. We analyzed these data longitudinally with mixed-effect modeling and also examined subsets of our cohorts for additional changes in T-cell effector function.Results Prior SARS-CoV-2 infection and female sex contributed to higher T-cell response in NHR but not HCW. When looking across time points, NHR but not HCW with prior infection had significantly higher T-cell responses than infection-naive subjects. These patterns of response were maintained across multiple booster vaccinations.Conclusions These results suggest that the age, multimorbidity, and/or frailty of the NHR cohort may accentuate sex and infection status differences in T-cell response to mRNA vaccination. T-cells responses in nursing home residents (NHR) and health care workers (HCW) after SARS-CoV-2 mRNA vaccination show that both groups have vaccine-induced responses, but prior infection and female sex contribute to higher responses in NHR but not HCW.