Memory B cell proliferation drives differences in neutralising responses between ChAdOx1 and BNT162b2 SARS-CoV-2 vaccines.

Vaccination against COVID-19 has been pivotal in reducing the global burden of the disease. However, Phase III trial results and observational studies underscore differences in efficacy across vaccine technologies and dosing regimens. Notably, mRNA vaccines have exhibited superior effectiveness compared to Adenovirus (AdV) vaccines, especially with extended dosing intervals. Using in-host mechanistic modelling, this study elucidates these variations and unravels the biological mechanisms shaping the immune responses at the cellular level. We used data on the change in memory B cells, plasmablasts, and antibody titres after the second dose of a COVID-19 vaccine for Australian healthcare workers. Alongside this dataset, we constructed a kinetic model of humoral immunity which jointly captured the dynamics of multiple immune markers, and integrated hierarchical effects into this kinetics model, including age, dosing schedule, and vaccine type. Our analysis estimated that mRNA vaccines induced 2.1 times higher memory B cell proliferation than AdV vaccines after adjusting for age, interval between doses and priming dose. Additionally, extending the duration between the second vaccine dose and priming dose beyond 28 days boosted neutralising antibody production per plasmablast concentration by 30%. We also found that antibody responses after the second dose were more persistent when mRNA vaccines were used over AdV vaccines and for longer dosing regimens. Reconstructing in-host kinetics in response to vaccination could help optimise vaccine dosing regimens, improve vaccine efficacy in different population groups, and inform the design of future vaccines for enhanced protection against emerging pathogens.

The Potential Benefits of Delaying Seasonal Influenza Vaccine Selections for the Northern Hemisphere: A Retrospective Modeling Study in the United States.

BACKGROUND: Antigenic similarity between vaccine viruses and circulating viruses is crucial for achieving high vaccine effectiveness against seasonal influenza. New non-egg-based vaccine production technologies could revise current vaccine formulation schedules. We aim to assess the potential benefit of delaying seasonal influenza vaccine virus selection decisions. METHODS: We identified seasons where season-dominant viruses presented increasing prevalence after vaccine formulation had been decided in February for the Northern Hemisphere, contributing to their antigenic discrepancy with vaccine viruses. Using a SEIR (susceptible-exposed-infectious-recovered) model of seasonal influenza in the United States, we evaluated the impact of updating vaccine decisions with more antigenically similar vaccine viruses on the influenza burden in the United States. RESULTS: In 2014-2015 and 2019-2020, the season-dominant A(H3N2) subclade and B/Victoria clade, respectively, presented increasing prevalence after vaccine decisions were already made for the Northern Hemisphere. Our model showed that the updated A(H3N2) vaccine could have averted 5000-65 000 influenza hospitalizations in the United States in 2014-2015, whereas updating the B/Victoria vaccine component did not substantially change influenza burden in the 2019-2020 season. CONCLUSIONS: With rapid vaccine production, revising current timelines for vaccine selection could result in substantial epidemiological benefits, particularly when additional data could help improve the antigenic match between vaccine and circulating viruses.

Hemagglutination Inhibition Antibody Titers as Mediators of Influenza Vaccine Efficacy Against Symptomatic Influenza A(H1N1), A(H3N2), and B/Victoria Virus Infections.

BACKGROUND: The hemagglutination inhibition antibody (HAI) titer contributes only a part of vaccine-induced protection against influenza virus infections. Using causal mediation analysis, we quantified the proportion of vaccine efficacy mediated by postvaccination HAI titers. METHODS: We conducted causal mediation analyses using data from a randomized, active-comparator controlled, phase III, trial of an inactivated, split-virion seasonal quadrivalent influenza vaccine in children conducted from October 2010 to December 2011 in 8 countries. Vaccine efficacy was estimated using a weighted Cox proportional hazards model. Estimates were decomposed into the direct and indirect effects mediated by postvaccination HAI titers. RESULTS: The proportions of vaccine efficacy mediated by postvaccination HAI titers were estimated to be 22% (95% confidence interval, 18%--47%) for influenza A(H1N1), 20% (16%-39%) for influenza A(H3N2), and 37% (26%-85%) for influenza B/Victoria. CONCLUSIONS: HAI titers partially mediate influenza vaccine efficacy against influenza A(H1N1), A(H3N2), and B/Victoria. Our estimates were lower than in previous studies, possibly reflecting expected heterogeneity in antigenic similarity between vaccine and circulating viruses across seasons.

Evaluating the impact of extended dosing intervals on mRNA COVID-19 vaccine effectiveness in adolescents.

Extending the dosing interval of a primary series of mRNA COVID-19 vaccination has been employed to reduce myocarditis risk in adolescents, but previous evaluation of impact on vaccine effectiveness (VE) is limited to risk after second dose. Here, we quantified the impact of the dosing interval based on case notifications and vaccination uptake in Hong Kong from January to April 2022. We estimated that the hazard ratio (HR) and odds ratio (OR) of infections after the second dose for extended (28 days or more) versus regular (21-27 days) dosing intervals ranged from 0.86 to 0.99 from calendar-time proportional hazards models, and from 0.85 to 0.87 from matching approaches, respectively. Adolescents in the extended dosing groups (including those who did not receive a second dose in the study period) had a higher hazard of infection than those with a regular dosing interval during the intra-dose period (HR: 1.66; 95% CI: 1.07, 2.59; p = 0.02) after the first dose. Implementing an extended dosing interval should consider multiple factors including the degree of myocarditis risk, the degree of protection afforded by each dose, and the extra protection achievable using an extended dosing interval.

An observational study on imported COVID-19 cases in Hong Kong during mandatory on-arrival hotel quarantine.

Background: Hong Kong enforced stringent travel restrictions during the COVID-19 pandemic. Understanding the characteristics of imported COVID-19 cases is important for establishing evidence-based control measures. Methods: Retrospective cohort study summarising the characteristics of imported cases detected in Hong Kong between 13 November 2020 and 31 January 2022, when compulsory quarantine was implemented. Findings: A total of 2269 imported COVID-19 cases aged 0-85 years were identified, of which 48.6 % detected on arrival. A shorter median delay from arrival to isolation was observed in Delta and Omicron cases (3 days) than in ancestral strain and other variants cases (12 days; p < 0.001). Lower Ct values at isolation were observed in Omicron cases than in ancestral strain or other variants cases. No Omicron cases were detected beyond 14 days after arrival. Cases detected after 14 days of quarantine (n=58, 2.6 %) were more likely asymptomatic at isolation and had higher Ct value during isolation, some of them indicating re-positivity or post-arrival infections. Conclusions: Testing inbound travellers at arrival and during quarantine can detect imported cases early, but may not prevent all COVID-19 introductions into the community. Public health measures should be adapted in response to the emergence of SARS-CoV-2 variants based on evidence from ongoing surveillance.

Prior infections and effectiveness of SARS-CoV-2 vaccine in test-negative studies: A systematic review and meta-analysis.

Prior infection with SARS-CoV-2 can provide protection against infection and severe COVID-19. We aimed to determine the impact of pre-existing immunity on the vaccine effectiveness (VE) estimates. We systematically reviewed and meta-analysed 66 test-negative design (TND) studies that examined VE against infection or severe disease (hospitalization, ICU admission, or death) for primary vaccination series. Pooled VE among studies that included people with prior COVID-19 infection was lower against infection (pooled VE: 77%; 95% confidence interval (CI): 72%, 81%) and severe disease (pooled VE: 86%; 95% CI: 83%, 89%), compared with studies that excluded people with prior COVID-19 infection (pooled VE against infection: 87%; 95% CI: 85%, 89%; pooled VE against severe disease: 93%; 95% CI: 91%, 95%). There was a negative correlation between VE estimates against infection and severe disease, and the cumulative incidence of cases before the start of the study or incidence rates during the study period. We found clear empirical evidence that higher levels of pre-existing immunity were associated with lower VE estimates. Prior infections should be treated as both a confounder and effect modificatory when the policies target the whole population or stratified by infection history, respectively.

Relative Vaccine Effectiveness of Cell- vs Egg-Based Quadrivalent Influenza Vaccine Against Test-Confirmed Influenza Over 3 Seasons Between 2017 and 2020 in the United States.

Background: Influenza vaccine viruses grown in eggs may acquire egg-adaptive mutations that may reduce antigenic similarity between vaccine and circulating influenza viruses and decrease vaccine effectiveness. We compared cell- and egg-based quadrivalent influenza vaccines (QIVc and QIVe, respectively) for preventing test-confirmed influenza over 3 US influenza seasons (2017-2020). Methods: Using a retrospective test-negative design, we estimated the relative vaccine effectiveness (rVE) of QIVc vs QIVe among individuals aged 4 to 64 years who had an acute respiratory or febrile illness and were tested for influenza in routine outpatient care. Exposure, outcome, and covariate data were obtained from electronic health records linked to pharmacy and medical claims. Season-specific rVE was estimated by comparing the odds of testing positive for influenza among QIVc vs QIVe recipients. Models were adjusted for age, sex, geographic region, influenza test date, and additional unbalanced covariates. A doubly robust approach was used combining inverse probability of treatment weights with multivariable regression. Results: The study included 31 824, 33 388, and 34 398 patients in the 2017-2018, 2018-2019, and 2019-2020 seasons, respectively; ∼10% received QIVc and ∼90% received QIVe. QIVc demonstrated superior effectiveness vs QIVe in prevention of test-confirmed influenza: rVEs were 14.8% (95% CI, 7.0%-22.0%) in 2017-2018, 12.5% (95% CI, 4.7%-19.6%) in 2018-2019, and 10.0% (95% CI, 2.7%-16.7%) in 2019-2020. Conclusions: This study demonstrated consistently superior effectiveness of QIVc vs QIVe in preventing test-confirmed influenza over 3 seasons characterized by different circulating viruses and degrees of egg adaptation.

Estimates of Seasonal Influenza Burden That Could Be Averted by Improved Influenza Vaccines in the Australian Population Aged Under 65 Years, 2015-2019.

BACKGROUND: The interpretation of relative vaccine effectiveness (rVE) of improved influenza vaccines is complex. Estimation of burden averted is useful to contextualise their potential impact across different seasons. For the population aged under 65 years in Australia, this study estimated the additional morbidity and mortality that could be averted using improved influenza vaccines. METHODS: We used observed, season-specific (2015-2019) influenza notification and influenza-coded hospitalisation frequencies and published modelled estimates of influenza-associated hospitalisations and deaths that occurred under the prevailing influenza vaccination coverage scenario. After back-calculating to the estimated burden in the population without vaccination, we applied published standard influenza vaccine effectiveness and coverage estimates to calculate the burden potentially averted by standard and improved influenza vaccines. A plausible range of rVE values were used, assuming 50% coverage. RESULTS: The percentage point difference in absolute vaccine effectiveness (VE) of an improved vaccine compared to a standard vaccine is directly proportional to its rVE and inversely proportional to the effectiveness of the standard vaccine. The incremental burden averted by an improved vaccine is a function of both its difference in absolute VE and the severity of the influenza season. Assuming an rVE of 15% with 50% coverage, the improved vaccine was estimated to additionally avert 1517 to 12,641 influenza notifications, 287 to 1311 influenza-coded hospitalisations and 9 to 33 modelled all-cause influenza deaths per year compared to the standard vaccine. CONCLUSIONS: Improved vaccines can have substantial clinical and population impact, particularly when the effectiveness of standard vaccines is low, and burden is high.

Influenza vaccine effectiveness against hospitalizations associated with influenza A(H3N2) in Hong Kong children aged 9 months to 17 years, June-November 2023.

A test negative study was carried out from 13 June through to 15 November 2023 enrolling 3183 children hospitalized with acute respiratory illness in Hong Kong. Influenza A and B viruses were detected in 528 (16.6%) children, among which 419 (79.4%) were influenza A(H3N2). The overall vaccine effectiveness against hospitalization associated with any influenza virus infection was estimated as 22.4% (95% CI: -11.7%, 46.1%), and against influenza A(H3N2) specifically was 14.3% (95% CI: -29.2%, 43.2%). Despite the moderate to low VE estimated here, which could be a result of waning immunity and antigenic drift, influenza vaccination remains an important approach to reduce the impact of influenza in children.

Quantifying the impact of pre-vaccination titre and vaccination history on influenza vaccine immunogenicity.

Epidemiological studies suggest that heterogeneity in influenza vaccine antibody response is associated with host factors, including pre-vaccination immune status, age, gender, and vaccination history. However, the pattern of reported associations varies between studies. To better understand the underlying influences on antibody responses, we combined host factors and vaccine-induced in-host antibody kinetics from a cohort study conducted across multiple seasons with a unified analysis framework. We developed a flexible individual-level Bayesian model to estimate associations and interactions between host factors, including pre-vaccine HAI titre, age, sex, vaccination history and study setting, and vaccine-induced HAI titre antibody boosting and waning. We applied the model to derive population-level and individual effects of post-vaccine antibody kinetics for vaccinating and circulating strains for A(H1N1) and A(H3N2) influenza subtypes. We found that post-vaccine HAI titre dynamics were significantly influenced by pre-vaccination HAI titre and vaccination history and that lower pre-vaccination HAI titre results in longer durations of seroprotection (HAI titre equal to 1:40 or higher). Consequently, for A(H1N1), our inference finds that the expected duration of seroprotection post-vaccination was 171 (95% Posterior Predictive Interval[PPI] 128-220) and 159 (95% PPI 120-200) days longer for those who are infrequently vaccinated (<2 vaccines in last five years) compared to those who are frequently vaccinated (2 or more vaccines in the last five years) at pre-vaccination HAI titre values of 1:10 and 1:20 respectively. In addition, we found significant differences in the empirical distributions that describe the individual-level duration of seroprotection for A(H1N1) circulating strains. In future, studies that rely on serological endpoints should include the impact of pre-vaccine HAI titre and prior vaccination status on seropositivity and seroconversion estimates, as these significantly influence an individual's post-vaccination antibody kinetics.

Key Challenges for Respiratory Virus Surveillance while Transitioning out of Acute Phase of COVID-19 Pandemic.

To support the ongoing management of viral respiratory diseases while transitioning out of the acute phase of the COVID-19 pandemic, many countries are moving toward an integrated model of surveillance for SARS-CoV-2, influenza virus, and other respiratory pathogens. Although many surveillance approaches catalyzed by the COVID-19 pandemic provide novel epidemiologic insight, continuing them as implemented during the pandemic is unlikely to be feasible for nonemergency surveillance, and many have already been scaled back. Furthermore, given anticipated cocirculation of SARS-CoV-2 and influenza virus, surveillance activities in place before the pandemic require review and adjustment to ensure their ongoing value for public health. In this report, we highlight key challenges for the development of integrated models of surveillance. We discuss the relative strengths and limitations of different surveillance practices and studies as well as their contribution to epidemiologic assessment, forecasting, and public health decision-making.

Risk of Severe Maternal Morbidity Associated With Severe Acute Respiratory Syndrome Coronavirus 2 Infection During Pregnancy.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy increases the risk of adverse fetal and neonatal outcomes, but the contribution to severe maternal morbidity (SMM) has been less frequently documented. Methods: We conducted a national cohort study of 93 624 deliveries occurring between 11 March 2020 and 1 July 2021 using medical claims information from the OptumLabs Data Warehouse. SARS-CoV-2 infection was identified from diagnostic and laboratory testing claims records. We identified 21 SMM conditions using International Classification of Diseases, Tenth Revision, Clinical Modification and procedure codes and compared SMM conditions by SARS-CoV-2 status using Poisson regression with robust variance, adjusting for maternal sociodemographic and health factors, onset of labor, and week of conception. Results: Approximately 5% of deliveries had a record of SARS-CoV-2 infection: 27.0% <7 days before delivery, 13.5% within 7-30 days of delivery, and 59.5% earlier in pregnancy. Compared to uninfected pregnancies, the adjusted risk of SMM was 2.22 times higher (95% confidence interval [CI], 1.97-2.48) among those infected <7 days before delivery and 1.66 times higher (95% CI, 1.23-2.08) among those infected 7-30 days before delivery. The highest risks were observed for acute respiratory distress syndrome (adjusted risk ratio [aRR], 13.24 [95% CI, 12.86-13.61]) and acute renal failure (aRR, 3.91 [95% CI, 3.32-4.50]). Conclusions: COVID-19 is associated with increased rates of SMM.