Search

Background: Respiratory syncytial virus (RSV) has been recognized recently as an important adult pathogen.Methods: This randomized, double-blind, placebo-controlled study was designed to compare humoral responses to licensed trivalent influenza vaccine given concomitantly with 1 of 2 RSV vaccine formulations in persons > or =65 years old with cardiopulmonary disease. Hemagglutinin-inhibition assays and neutralization assays were used to measure levels of antibody to influenza and RSV, respectively. Subjects with respiratory illnesses during subsequent winters were tested for RSV and influenza by reverse-transcriptase polymerase chain reaction and serologic analysis.Results: Neither RSV vaccine formulation had an effect on the humoral response to influenza vaccination, and both RSV vaccines were well tolerated by 1169 participants. The immunogenicity of the nonadjuvanted vaccine was judged superior on the basis of mean postvaccination neutralizing antibody titers (12.5 vs. 12.1) and the percentage of subjects for whom > or =4-fold increases in neutralizing titer were observed when acute-phase and convalescent-phase serum samples were compared (168 [44%] of 383 vs. 129 [33%] of 400). In year 1, the percentage of illnesses due to RSV was 7% (36 of 492 illnesses) and that due to influenza was 8% (40 of 492), compared with 6% (11 of 189) due to RSV and 11% (20 of 189) due to influenza in year 2. The incidence of RSV infection was not significantly different in the RSV vaccine and placebo groups.Conclusions: Although the safety and immunogenicity data of these RSV vaccines are encouraging, low rates of infection make it challenging to design efficacy trials. [ABSTRACT FROM AUTHOR]

Background. Two doses of trivalent inactivated influenza vaccine (TIV) are recommended for children <9 years old receiving vaccine for the first time, but compliance is suboptimal. This study assessed the need for a second dose of TIV in this age group.Methods. In this prospective, open-label study, 232 influenza vaccine-naive 5-8-year-olds enrolled in a health maintenance organization received 2 doses of TIV in fall 2004. Serum for antibody titer measurement was obtained at 3 time points (n=222). Parents completed diaries for 5 days.Results. Both doses of vaccine were well tolerated. The strongest predictor of a protective antibody response (>/=1 : 40) after 1 dose of TIV was baseline seropositive status. In multivariate analysis adjusting for age, sex, and baseline serostatus, the proportion of children with protective antibody responses was significantly higher after 2 doses than after 1 dose of TIV for each antigen (P<.001, for A/H1N1; P=.01, for A/H3N2; P<.001, for B). Age and sex were not independently predictive of a protective antibody response. Over one-third of children had antibody responses <1:40 for the type B vaccine component, even after 2 doses.Conclusions. The present study supports the need for 2 doses of TIV in 5-8-year-olds receiving TIV for the first time. Efforts to increase compliance with the 2-dose recommendation are warranted. Copyright © 2006 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

Objectives: A population-based assessment of maternal and perinatal morbidity related to respiratory illness during influenza season among pregnant women has not been published. The objectives of this investigation were to describe and quantify the impact of respiratory hospitalization during pregnancy on serious maternal and perinatal morbidity.Study Design: A matched cohort study using an administrative database of pregnant women enrolled in the Tennessee Medicaid population to determine pregnancy outcomes associated with respiratory hospitalizations during influenza season. Pregnant women aged 15 to 44 years with a respiratory hospitalization during influenza seasons 1985-1993 were matched by gestational age and presence of comorbidity with pregnant control subjects without a respiratory hospitalization.Results: During the eight influenza seasons studied, 293 women with singleton pregnancies had respiratory disease hospitalizations (5.1:1000). Women with asthma had high rates of such hospitalization (59.7:1000). Compared with matched controls, women with respiratory hospitalizations had similar modes of delivery, delivery length of stay, and episodes of preterm labor. The prevalence of prematurity and low birth weight among infants born to such women was likewise similar between the two groups.Conclusion: In this population of pregnant women, those with asthma accounted for half of all respiratory-related hospitalizations during influenza seasons, with 6% of pregnant women with asthma requiring respiratory hospitalization during influenza season, (odds ratio 10.63, 95% CI, 8.18-13.83, compared with women without a medical comorbidity). We detected no significant increase in adverse perinatal outcomes associated with respiratory hospitalizations during influenza season. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Immunoprophylaxis with influenza vaccine is the primary method for reducing the effect of influenza on children, and inactivated influenza vaccine has been shown to be safe and effective in children. The Advisory Committee on Immunization Practices recommends that children 6 to 23 months of age who are receiving trivalent inactivated influenza vaccine for the first time be given 2 doses; however, delivering 2 doses of trivalent inactivated influenza vaccine > or = 4 weeks apart each fall can be logistically challenging. We evaluated an alternate spring dosing schedule to assess whether a spring dose of trivalent inactivated influenza vaccine was capable of 'priming' the immune response to a fall dose of trivalent inactivated influenza vaccine containing 2 different antigens. PATIENTS AND METHODS: Healthy children born between November 1, 2002, and December 31, 2003, were recruited in the spring and randomly assigned to either the alternate spring schedule or standard fall schedule. The 2003-2004 licensed trivalent inactivated influenza vaccine was administered in the spring; the fall 2004-2005 vaccine had the same A/H1N1 antigen but contained drifted A/H3N2 antigen and B antigen with a major change in strain lineage. Reactogenicity was assessed by parental diaries and telephone surveillance. Blood was obtained after the second dose of trivalent inactivated influenza vaccine for all of the children and after the first dose of trivalent inactivated influenza vaccine in the fall group. The primary outcome of this study was to demonstrate noninferiority of the antibody response after a spring-fall dosing schedule compared with the standard fall dosing schedule. Noninferiority was based on the proportion of subjects in each group achieving a hemagglutination-inhibition antibody titer of > or = 1:32 after vaccination to 2 of the 3 antigens (H1N2, H3N2, and B) contained in the 2004-2005 vaccine. For each antigen, the antibody response was proposed to be noninferior if, within the upper bound of 95% confidence interval, there was < 15% difference between the proportion of children in the fall and spring groups with postvaccination titers > or = 1:32. RESULTS: A total of 468 children were randomly assigned to either the spring (n = 233) or fall (n = 235) trivalent inactivated influenza vaccine schedule. Excellent response rates to A/H1N1, as measured by antibody levels > or = 1:32, were noted in both the spring (86%) and fall groups (93%). The A/H1N1 response rate of the spring group was noninferior to that of the fall group. Noninferiority of the spring schedule was not met with respect to the other 2 influenza antigens: for A/H3N2 the response was 70% in the spring group versus 83% for the fall group, and the response to B was 39% in the spring group versus 88% for the fall group. After 2 doses of vaccine, the geometric mean antibody titers also were less robust in the spring group for both A/H3N2 and B antigens. For each of the 3 vaccine antigens, the respective geometric mean antibody titers for the spring group versus the fall group were: A/H1N1, 79.5 +/- 3.3 and 91.9 +/- 2.6; A/H3N2, 57.1 +/- 4.1 and 77.8 +/- 3.7; and B, 18.0 +/- 2.4 and 61.6 +/- 2.5. However, a significantly higher proportion of children in the spring group achieved potentially protective levels of antibody to all 3 antigens after their first fall dose of trivalent inactivated influenza vaccine than children in the fall group after receiving their first fall dose. For influenza A/H1N1, there was an antibody level > or = 1:32 in 86% of children in the spring group versus 55% of children in the fall group. Likewise, for influenza A/H3N2, 70% of children in the spring group and 47% of children in the fall group had antibody levels > 1:32; for influenza B, the proportions were 39% of children in the spring group and 16% of children in the fall group. Reactogenicity after trivalent inactivated influenza vaccine in both groups of children was minimal and did not differ by dose. CONCLUSIONS: Although the immune response to the identical A/H1N1 vaccine antigen was similar in both groups, priming with different A/H3N2 antigens and B antigens in the spring produced a lower immune response to both antigens than that shown in children who received 2 doses of the same vaccine in the fall. However, approximately 70% of children in the spring group had a protective response to the H3N2 antigen after 2 doses. Initiating influenza immunization in the spring was superior to 1 dose of trivalent inactivated influenza vaccine in the fall. The goal of delivering 2 doses of influenza vaccine a month apart to vaccine-naive children within the narrow flu vaccination season is a challenge not yet met; thus far, only about half of children aged 6 to 23 months of age are receiving influenza vaccine. By using the spring schedule, we were able to administer 2 doses of trivalent inactivated influenza vaccine to a higher proportion of children earlier in the influenza vaccination season. In years when there is an ample supply of trivalent inactivated influenza vaccine, and vaccine remains at the end of the season, priming influenza vaccine-naive infants with a spring dose will lead to the earlier protection of a higher proportion of infants in the fall. This strategy may be particularly advantageous when there is an early start to an influenza season as occurred in the fall of 2003. A priming dose of influenza vaccine in the spring may also offer other advantages. Many vaccine-naive children may miss the second dose of fall trivalent inactivated influenza vaccine because of vaccine shortages or for other reasons, such as the potential implementation of new antigens at a late date. Even with seasonal changes in influenza vaccine antigens, by giving a springtime dose of trivalent inactivated influenza vaccine, such children would be more protected against influenza than would children who were only able to receive 1 dose in the fall. In summary, our data suggest that identical influenza antigens are not necessary for priming vaccine-naive children and that innovative uses of influenza vaccine, such as a springtime dose of vaccine, could assist in earlier and more complete immunization of young children. [ABSTRACT FROM AUTHOR]

BACKGROUND: Pneumonia is a common complication of influenza infection in elderly individuals and could therefore potentially be prevented by influenza vaccination. In studies with data from administrative sources, vaccinated elderly people had a reduced risk of admission for pneumonia compared with unvaccinated seniors; however, these findings could have been biased by underlying differences in health between the groups. Furthermore, since most individuals with pneumonia are not treated in hospital, such studies should include both outpatient and inpatient events. We therefore assessed whether influenza vaccination is associated with a reduced risk of community-acquired pneumonia in immunocompetent elderly people after controlling for health status indicators. METHODS: We did a population-based, nested case-control study in immunocompetent elderly people aged 65-94 years (cases and controls) enrolled in Group Health (a health maintenance organisation) during the 2000, 2001, and 2002 preinfluenza periods and influenza seasons. Cases were individuals with an episode of outpatient or inpatient community-acquired pneumonia (validated by review of medical records or chest radiograph reports). We randomly selected two age-matched and sex-matched controls for each case. The exposure of interest was influenza vaccination. We reviewed medical records to define potential confounders, including smoking history, presence and severity of lung and heart disease, and frailty indicators. FINDINGS: 1173 cases and 2346 controls were included in the study. After we adjusted for the presence and severity of comorbidities, as defined by chart review, influenza vaccination was not associated with a reduced risk of community-acquired pneumonia (odds ratio 0.92, 95% CI 0.77-1.10) during the influenza season. INTERPRETATION: The effect of influenza vaccination on the risk of pneumonia in elderly people during influenza seasons might be less than previously estimated. FUNDING: Group Health Center for Health Studies internal funds and Group Health Community Foundation fellowship grant. [ABSTRACT FROM AUTHOR]

Vaccine safety and immunogenicity data in human immunodeficiency virus (HIV)-exposed uninfected (HEU) children are important for decision-making in HIV and typhoid co-endemic countries. In an open-label study, we recruited Malawian HEU and HIV unexposed uninfected (HUU) infants aged 9 - 11 months. HEU participants were randomized to receive Vi-tetanus toxoid conjugate vaccine (Vi-TT) at 9 months, Vi-TT at 15 months, or Vi-TT at 9 and 15 months. HUU participants received Vi-TT at 9 and 15 months. Safety outcomes included solicited and unsolicited adverse events (AE) and serious AEs (SAEs) within 7 days, 28 days, and 6 months of vaccination, respectively. Serum was collected before and at day 28 after each vaccination to measure anti-Vi IgG antibodies by enzyme-linked immunosorbent assay (ELISA). Cohort 1 (66 participants) enrollment began 02 December 2019, and follow-up was terminated before completion due to the COVID-19 pandemic. Cohort 2 (100 participants) enrollment began 25 March 2020. Solicited AEs were mostly mild, with no significant differences between HEU and HUU participants or one- and two-dose groups. All six SAEs were unrelated to vaccination. Anti-Vi geometric mean titers (GMT) increased significantly from 4.1 to 4.6 ELISA units (EU)/mL at baseline to 2572.0 - 4117.6 EU/mL on day 28 post-vaccination, and similarly between HEU and HUU participants for both one- and two-dose schedules. All participants seroconverted (>4-fold increase in GMT) by the final study visit. Our findings of comparable safety and immunogenicity of Vi-TT in HUU and HEU children support country introductions with single-dose Vi-TT in HIV-endemic countries.

In the phase 3 Coronavirus Efficacy (COVE) trial (NCT04470427), post-dose two Ancestral Spike-specific binding (bAb) and neutralizing (nAb) antibodies were shown to be correlates of risk (CoR) and of protection against Ancestral-lineage COVID-19 in SARS-CoV-2 naive participants. In the SARS-CoV-2 Omicron era, Omicron subvariants with varying degrees of immune escape now dominate, seropositivity rates are high, and booster doses are administered, raising questions on whether and how these developments affect the bAb and nAb correlates. To address these questions, we assess post-boost BA.1 Spike-specific bAbs and nAbs as CoRs and as correlates of booster efficacy in COVE. For naive individuals, bAbs and nAbs inversely correlate with Omicron COVID-19: hazard ratios (HR) per 10-fold marker increase (95% confidence interval) are 0.16 (0.03, 0.79) and 0.31 (0.10, 0.96), respectively. In non-naive individuals the analogous results are similar: 0.15 (0.04, 0.63) and 0.28 (0.07, 1.08). For naive individuals, three vs two-dose booster efficacy correlates with predicted nAb titer at exposure, with estimates -8% (-126%, 48%), 50% (25%, 67%), and 74% (49%, 87%), at 56, 251, and 891 Arbitrary Units/ml. These results support the continued use of antibody as a surrogate endpoint., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Coronavirus disease 2019 (COVID-19) vaccines reduce severe disease and mortality and may lessen transmission, measured by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load (VL). Evaluating vaccine associations in VL at COVID-19 diagnosis in 4 phase 3 randomized, placebo-controlled vaccine trials, July 2020 to July 2021, VL reductions were 2.78 log10 copies/mL (95% confidence interval [CI], 1.38-4.18; n = 60 placebo, 11 vaccine) and 2.12 log10 copies/mL (95% CI, 1.44-2.80; n = 594 placebo, 36 vaccine) for NVX-CoV2373 and mRNA-1273, respectively. Associations were not significant for AZD1222 (0.59 log10 copies/mL; 95% CI, -.19 to 1.36; n = 90 placebo, 78 vaccine) or Ad26.COV2.S (0.23 log10 copies/mL; 95% CI, -.01 to .47; n = 916 placebo, 424 vaccine). Thus, vaccines potentially decreased transmission when ancestral SARS-CoV-2 predominated. Clinical Trials Registration. NCT04470427, NCT04505722, NCT04516746, NCT04611802., Competing Interests: Potential conflicts of interest. A. F. had/has research grants from Pfizer, Merck, Janssen, CyanVac, VaxCo, Moderna, and BioFire Diagnostics; fees for advisory boards from GSK, ADMA Biologics, and Sanofi Pasteur; and fees for data safety monitoring board from Novavax. M. E. S. had/has grants from the National Institutes of Health (NIH) and National Institute of Allergy and Infectious Diseases (NIAID) during the conduct of the study (5UM1AI069470); grants from NIH/NIAID and Gates Foundation outside the submitted work; and grants to her institution from Merck Sharpe and Dohme, Sanofi, and Gilead outside of the submitted work. S. R. W. has received institutional funding from the NIH/NIAID; institutional grants or contracts from Sanofi Pasteur, Janssen Vaccines/Johnson & Johnson, Moderna Tx, Pfizer, Vir Biotechnology, and Worcester HIV Vaccine; has participated on data safety monitoring or advisory boards for Janssen Vaccines/Johnson & Johnson and BioNTech; and his spouse holds stock/stock options in Regeneron Pharmaceuticals. C. M. E. has received research grants from Merck and AstraZeneca; and has participated in Sanofi, Janssen, and Gilead advisory board meetings. N. R. is a paid safety consultant for ICON, CyanVac, and EMMES; served on selected advisory boards for Sanofi, Seqirus, Pfizer, and Moderna; and receives funds to their institution to conduct research from Sanofi, Lilly, Merck, Quidel, Immorna, Vaccine Company, and Pfizer. C. L. G. has received institutional funding from the NIH for the conduct of the Moderna and Novavax studies; and grants to her institution from Gilead and ViiV outside of the submitted work. K. L. K. has received institutional funding from the NIH for the conduct of the Moderna and Novavax studies (UM1 AI 148689); and from Novavax outside of the submitted work. J. A. G. is employed by and holds stock in AstraZeneca. E. A. H. received fees from Oxford University for time spent adjudicating end points for the AstraZeneca/Oxford SARS-CoV-2 vaccine trials conducted in the UK, South Africa, and Brazil. M. D. T. has received institutional funding from the NIH for the conduct of the Moderna and Novavax studies (UM1 AI 148689). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Although the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are highly efficacious at preventing severe disease in the general population, current data are lacking regarding vaccine efficacy (VE) for individuals with mild immunocompromising conditions., Methods: A post hoc, cross-protocol analysis of participant-level data from the blinded phase of four randomized, placebo-controlled, coronavirus disease 2019 (COVID-19) vaccine phase 3 trials (Moderna, AstraZeneca, Janssen, and Novavax) was performed. We defined a "tempered immune system" (TIS) variable via a consensus panel based on medical history and medications to determine VE against symptomatic and severe COVID-19 cases in TIS participants versus non-TIS individuals starting at 14 days after completion of the primary series through the blinded phase for each of the 4 trials. An analysis of participants living with well-controlled human immunodeficiency virus was conducted using the same methods., Results: A total of 3852/30 351 (12.7%) Moderna participants, 3088/29 868 (10.3%) Novavax participants, 3549/32 380 (11.0%) AstraZeneca participants, and 5047/43 788 (11.5%) Janssen participants were identified as having a TIS. Most TIS conditions (73.9%) were due to metabolism and nutritional disorders. Vaccination (vs placebo) significantly reduced the likelihood of symptomatic and severe COVID-19 for all participants for each trial. VE was not significantly different for TIS participants versus non-TIS for either symptomatic or severe COVID-19 for each trial, nor was VE significantly different in the symptomatic endpoint for participants with human immunodeficiency virus., Conclusions: For individuals with mildly immunocompromising conditions, there is no evidence of differences in VE against symptomatic or severe COVID-19 compared with those with non-TIS in the 4 COVID-19 vaccine randomized controlled efficacy trials., Competing Interests: Potential conflicts of interest. O. A. received salary support from research funding paid to UCLA by Moderna, Inc. A. T. reports that this project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. C. L. G.’s institution received funding from the NIH for salary support for her role as site Principal Investigator for the Moderna Phase 3 trial and site Principle and Co-Chair for the Novavax Phase 3 trial. N. R. received research grants from Pfizer, Merck, Sanofi, Quidel, Immorna, Vaccine Company, and Lilly through her institution, consulting fees from Krog, honoraria as speaker for Virology education, and travel support from Sanofi and Moderna. N. R. serves on safety committees for ICON and EMMES and is a member of the Moderna, Sanofi, Seqirus, and Pfizer selected Advisory boards. I. H. is an employee of AstraZeneca and holds/may hold stock in AstraZeneca. A. R. F. reports grant support from Janssen, Pfizer, Moderna, CyanVac, VaxCo, and BioFire Diagnostics; advisory board fees from Arrowhead and GSK; travel reimbursement from GSK and Sanofi and fees for DSMB from Novavax. B. L. is an employee of Moderna, Inc. and may own stock/stock options in the company. J. S. declares support for the submitted work from the Janssen Pharmaceutical Companies of Johnson & Johnson and partial support (in the form of funding to his institution) from BARDA for the submitted work, declares support from the Janssen Pharmaceutical Companies of Johnson & Johnson and BARDA funding for part of this work, has patents on invention of the Janssen COVID-19 vaccine, and has Johnson & Johnson stock and stock options. P. A. G. reports a patent for a COVID-19 monoclonal antibody from Aridis Pharmaceuticals. V. C. reports payments made to Emory University from Gilead Sciences. K. N. receives grants from NIH to participate in overall organization of COVID vaccine trials and for participation in vaccine trials and has a grant for Vaxco for a phase 1 testing of a broadly reactive COVID-19 vaccine. L. D. is an employee of Novavax, Inc. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Typhoid fever is responsible for a substantial health burden in low- and middle-income countries (LMICs). New means of prevention became available with the prequalification of typhoid conjugate vaccines (TCV) by the World Health Organization (WHO) in 2018. Policymakers require evidence to inform decisions about TCV. The economic burden related to typhoid fever can be considerable, both for healthcare providers and households, and should be accounted for in the decision-making process. We aimed to understand the breadth of the evidence on the cost of typhoid fever by undertaking a scoping review of the published literature. We searched scientific databases with terms referring to typhoid fever cost of illness to identify published studies for the period January 1st 2000 to May 24th 2024. We also conferred with stakeholders engaged in typhoid research to identify studies pending completion or publication. We identified 13 published studies reporting empirical data for 11 countries, most of them located in Asia. The total cost of a typhoid episode ranged from $23 in India to $884 in Indonesia (current 2022 United States Dollar [USD]). Household expenditures related to typhoid fever were characterized as catastrophic in 9 studies. We identified 5 studies pending completion or publication, which will provide evidence for 9 countries, most of them located in Africa. Alignment in study characteristics and methods would increase the usefulness of the evidence generated and facilitate cross-country and regional comparison. The gap in evidence across regions should be mitigated when studies undertaken in African countries are published. There remains a lack of evidence on the cost to treat typhoid in the context of increasing antimicrobial resistance. Decision-makers should consider the available evidence on the economic burden of typhoid, particularly as risk factors related to antimicrobial resistance and climate change increase typhoid risk. Additional studies should address typhoid illness costs, using standardized methods and accounting for the costs of antimicrobial resistance., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Debellut et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Competing Interests: KMN is the Chair of the Data and Safety Monitoring Board for the Pfizer mRNA influenza vaccine trial. LC declares no competing interests.

Importance: SARS-CoV-2 viral load (VL) in the nasopharynx is difficult to quantify and standardize across settings, but it may inform transmission potential and disease severity., Objective: To characterize VL at COVID-19 diagnosis among previously uninfected and unvaccinated individuals by evaluating the association of demographic and clinical characteristics, viral variant, and trial with VL, as well as the ability of VL to predict severe disease., Design, Setting, and Participants: This secondary cross-protocol analysis used individual-level data from placebo recipients from 4 harmonized, phase 3 COVID-19 vaccine efficacy trials sponsored by Moderna, AstraZeneca, Janssen, and Novavax. Participants were SARS-CoV-2 negative at baseline and acquired COVID-19 during the blinded phase of the trials. The setting included the US, Brazil, South Africa, Colombia, Argentina, Peru, Chile, and Mexico; start dates were July 27, 2020, to December 27, 2020; data cutoff dates were March 26, 2021, to July 30, 2021. Statistical analysis was performed from November 2022 to June 2023., Main Outcomes and Measures: Linear regression was used to assess the association of demographic and clinical characteristics, viral variant, and trial with polymerase chain reaction-measured log10 VL in nasal and/or nasopharyngeal swabs taken at the time of COVID-19 diagnosis., Results: Among 1667 participants studied (886 [53.1%] male; 995 [59.7%] enrolled in the US; mean [SD] age, 46.7 [14.7] years; 204 [12.2%] aged 65 years or older; 196 [11.8%] American Indian or Alaska Native, 150 [9%] Black or African American, 1112 [66.7%] White; 762 [45.7%] Hispanic or Latino), median (IQR) log10 VL at diagnosis was 6.18 (4.66-7.12) log10 copies/mL. Participant characteristics and viral variant explained only 5.9% of the variability in VL. The independent factor with the highest observed differences was trial: Janssen participants had 0.54 log10 copies/mL lower mean VL vs Moderna participants (95% CI, 0.20 to 0.87 log10 copies/mL lower). In the Janssen study, which captured the largest number of COVID-19 events and variants and used the most intensive post-COVID surveillance, neither VL at diagnosis nor averaged over days 1 to 28 post diagnosis was associated with COVID-19 severity., Conclusions and Relevance: In this study of placebo recipients from 4 randomized phase 3 trials, high variability was observed in SARS-CoV-2 VL at the time of COVID-19 diagnosis, and only a fraction was explained by individual participant characteristics or viral variant. These results suggest challenges for future studies of interventions seeking to influence VL and elevates the importance of standardized methods for specimen collection and viral load quantitation.

Pertussis (whooping cough) is a reemergent, highly contagious respiratory infection of public health concern. Infants prior to initiation of their primary vaccination series are the most vulnerable to severe infection, and even death. Vaccination during pregnancy is an efficacious means of reducing infection in infants. This approach relies on boosting maternal immunity and passive transfer of antibodies to the infant via placenta and breast milk. Similarly, maternal vaccination post-partum can enhance maternal-infant immunity. To support the analysis of pertussis immunity in the context of maternal-infant immunization, we developed a high throughput multiplex assay for simultaneous quantification of serum IgG antibodies against pertussis vaccine antigens: pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin (PRN), and fimbriae (FIM2/3), and against tetanus (TT) and diphtheria toxoids (DT), using the Meso Scale Discovery (MSD) platform. The assay was qualified, and specificity, sensitivity, accuracy, precision, linearity, and robustness were demonstrated. The assay was subsequently adapted for quantification of IgG and IgA in breast milk. Applied to a serological survey of pregnant women living in the United States and sub-Saharan Africa, this method revealed differences in magnitude and breadth of antibody profile, consistent with history of vaccination. A longitudinal analysis of Tdap responses in women vaccinated post-partum demonstrated a rapid increase in serum IgG that remained elevated for up to 24 months. Likewise, high levels of vaccine-specific IgA and IgG antibodies were present in breast milk, although they exhibited faster decay. This multiplex MSD assay is a reliable and practical tool for quantification of pertussis, tetanus, and diphtheria antibodies in serum and breast milk in serosurveys or vaccine studies., Importance: Pertussis (whooping cough) has reemerged in recent years. Vaccination during pregnancy is an effective approach to prevent illness during the first months of life. We developed a multiplex assay for quantification of pertussis, tetanus, and diphtheria serum antibodies using the Meso Scale Discovery (MSD) platform; the method was qualified, and specificity, precision, accuracy, linearity, and limits of quantification were defined. It was also adapted for quantification of antibodies in breast milk. We successfully determined serostatus in women from different regions and with different vaccination histories, as well as responses to Tdap in blood and breast milk post-partum. This is the first description of a multiplex assay for the quantification of pertussis, tetanus, and diphtheria antibodies in breast milk., Competing Interests: The authors declare no conflict of interest.

Typhoid intestinal perforation (TIP) is a leading cause of peritonitis and indication for emergency surgery in Africa, with reported mortality rates up to 30% in pediatric patients. Currently, data on TIP in Western databases are primarily from countries that speak English, likely due to non-English publication and citation biases. Despite the high burden of infectious diseases in Francophone Africa, data from these countries regarding TIP remain limited. This study aims to highlight the incidence and morbidity of TIP in Francophone African countries using an extended search algorithm. We conducted a scoping review using the PubMed, EMBASE, and SCOPUS databases with the keywords "peritonitis", "non-traumatic ileal perforation", and "typhoid" in Francophone African countries. Additionally, we contacted surgeons in Africa and concurrently used citation chasing to obtain data not found in western databases. In total, 32 studies from 12 countries were identified and included in this review. A total of 22 publications were in French. Patient median age was 20 years and TIP caused a median of 35% of acute peritonitis cases. Mortality rates ranged from 6-37% (median: 16%). Rate of complications ranged from 15-92% (median: 46%). Ileostomy creation as a treatment for TIP varied between hospitals (0-79%), with the highest rates reported in Niger. In Francophone Africa, TIP is associated with high morbidity and mortality, most commonly in children and young adults. Interventions, including improved sanitation and the introduction of typhoid conjugate vaccines into routine vaccination programs, have the potential to significantly decrease typhoid fever and its complications., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Sukri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: While maternal pertussis vaccination is a strategy to reduce infant morbidity, safety and immunogenicity data are limited in sub-Saharan Africa. We aimed to evaluate the safety of a single dose of tetanus, diphtheria and acellular pertussis vaccine (Tdap) vaccine compared to tetanus and diphtheria vaccine (Td) vaccine in pregnant women in Bamako, Mali and to assess the pertussis toxin (PT) antibody response at birth., Methods: In this phase 2, single-centre, randomised, double-blind, active-controlled study, from 23 January 2019 to 10 July 2019, healthy 18-39 year old women in the second trimester of a singleton pregnancy were randomised 2:1 to receive Tdap or Td. Blood was tested for serum immunoglobulin G (IgG) against PT and other vaccine antigens using a qualified Meso Scale Discovery multiplex immunoassay. The co-primary objectives evaluated safety and birth anti-PT levels. Infant immune responses to whole-cell pertussis vaccine (DTwP) were assessed. Statistical analysis was descriptive. This trial is registered with clinicaltrials.gov, NCT03589768., Findings: 133 women received Tdap and 67 received Td, with 126 and 66 livebirths, respectively. In the Tdap group, 22 serious adverse events (SAEs) including one maternal death occurred in 20 participants (15·0%), with 10 SAEs in 10 participants (14·9%) in the Td group. Among infants, 18 events occurred among 13 participants (10.3%) and 8 SAEs in 6 participants (9.1%), including three and two infant deaths, occurred in Tdap and Td groups, respectively. None were related to study vaccines. Anti-PT geometric mean concentration (GMC) at birth in the Tdap group was higher than in the Td group (55.4 [46.2-66.6] IU/ml vs 7.9 [5.4-11.5] IU/ml). One month after the third dose of DTwP, the GMC in infants born to mothers in the Tdap group were lower compared to the Td group (20.2 [13.7-29.9] IU/ml vs 77.2 [32.2-184.8] IU/ml). By 6 months of age, the anti- PT GMCs were 17.3 [12.8-23.4] IU/ml and 67.1 [35.5-126.7] IU/ml in Tdap and Td groups, respectively. At birth, anti-tetanus toxin (TT) GMCs were higher in infants in the Td vs Tdap group (5.9 [5.0-7.0] IU/ml vs 4.1 [3.5-4.8] IU/ml). Anti-diphtheria toxin GMCs were similar in both groups., Interpretation: Tdap administered to pregnant women in Mali is safe and well-tolerated. Infants of mothers who received Tdap were born with high PT and protective anti-TT antibody levels. By six months of age, after primary vaccination, the PT levels were lower in the Tdap group compared to the Td group. The blunted immune responses to primary DTwP vaccination in the Tdap infant group warrant further study., Funding: This project was funded by National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), under contract numbers 75N93021C00012 (The Emmes Company), and HHSN27220130000221 (University of Maryland, Baltimore). Dr. Susana Portillo was supported by NIH award no. T32AI007524. NIAID, NIH provided Tdap vaccine (BOOSTRIX)., Competing Interests: We declare no competing interests except for KLK, who reports funding to conduct this research from NIAID to her institution., (© 2024 The Authors.)

In the ENSEMBLE randomized, placebo-controlled phase 3 trial (NCT04505722), estimated single-dose Ad26.COV2.S vaccine efficacy (VE) was 56% against moderate to severe-critical COVID-19. SARS-CoV-2 Spike sequences were determined from 484 vaccine and 1,067 placebo recipients who acquired COVID-19. In this set of prespecified analyses, we show that in Latin America, VE was significantly lower against Lambda vs. Reference and against Lambda vs. non-Lambda [family-wise error rate (FWER) p < 0.05]. VE differed by residue match vs. mismatch to the vaccine-insert at 16 amino acid positions (4 FWER p < 0.05; 12 q-value ≤ 0.20); significantly decreased with physicochemical-weighted Hamming distance to the vaccine-strain sequence for Spike, receptor-binding domain, N-terminal domain, and S1 (FWER p < 0.001); differed (FWER ≤ 0.05) by distance to the vaccine strain measured by 9 antibody-epitope escape scores and 4 NTD neutralization-impacting features; and decreased (p = 0.011) with neutralization resistance level to vaccinee sera. VE against severe-critical COVID-19 was stable across most sequence features but lower against the most distant viruses., (© 2024. The Author(s).)

Background and Objectives: Maternal vaccination may prevent infant coronavirus disease 2019 (COVID-19). We aimed to quantify protection against infection from maternally derived vaccine-induced antibodies in the first 6 months of an infant's life., Methods: Infants born to mothers vaccinated during pregnancy with 2 or 3 doses of a messenger RNA COVID-19 vaccine (nonboosted or boosted, respectively) had full-length spike (Spike) immunoglobulin G (IgG), pseudovirus 614D, and live virus D614G, and omicron BA.1 and BA.5 neutralizing antibody (nAb) titers measured at delivery. Infant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was determined by verified maternal-report and laboratory confirmation through prospective follow-up to 6 months of age between December 2021 and July 2022. The risk reduction for infection by dose group and antibody titer level was estimated in separate models., Results: Infants of boosted mothers (n = 204) had significantly higher Spike IgG, pseudovirus, and live nAb titers at delivery than infants of nonboosted mothers (n = 271), and were 56% less likely to acquire infection in the first 6 months (P = .03). Irrespective of boost, for each 10-fold increase in Spike IgG titer at delivery, the infant's risk of acquiring infection was reduced by 47% (95% confidence interval 8%-70%; P = .02). Similarly, a 10-fold increase in pseudovirus titers against Wuhan Spike, and live virus nAb titers against D614G, and omicron BA.1 and BA.5 at delivery were associated with a 30%, 46%, 56%, and 60% risk reduction, respectively., Conclusions: Higher transplacental binding and nAb titers substantially reduced the risk of SARS-CoV-2 infection in infants, and a booster dose amplified protection during a period of omicron predominance. Until infants are age-eligible for vaccination, maternal vaccination provides passive protection against symptomatic infection during early infancy., (Copyright © 2024 by the American Academy of Pediatrics.)

Background: Randomised controlled trials of typhoid conjugate vaccines among children in Africa and Asia have shown high short-term efficacy. Data on the durability of protection beyond 2 years are sparse. We present the final analysis of a randomised controlled trial in Malawi, encompassing more than 4 years of follow-up, with the aim of investigating vaccine efficacy over time and by age group., Methods: In this phase 3, double-blind, randomised controlled efficacy trial in Blantyre, Malawi, healthy children aged 9 months to 12 years were randomly assigned (1:1) by an unmasked statistician to receive a single dose of Vi polysaccharide conjugated to tetanus toxoid vaccine (Vi-TT) or meningococcal capsular group A conjugate (MenA) vaccine. Children had to have no previous history of typhoid vaccination and reside in the study areas for inclusion and were recruited from government schools and health centres. Participants, their parents or guardians, and the study team were masked to vaccine allocation. Nurses administering vaccines were unmasked. We did surveillance for febrile illness from vaccination until follow-up completion. The primary outcome was first occurrence of blood culture-confirmed typhoid fever. Eligible children who were randomly assigned and vaccinated were included in the intention-to-treat analyses. This trial is registered at ClinicalTrials.gov, NCT03299426., Findings: Between Feb 21, 2018, and Sept 27, 2018, 28 130 children were vaccinated; 14 069 were assigned to receive Vi-TT and 14 061 to receive MenA. After a median follow-up of 4·3 years (IQR 4·2-4·5), 24 (39·7 cases per 100 000 person-years) children in the Vi-TT group and 110 (182·7 cases per 100 000 person-years) children in the MenA group were diagnosed with a first episode of blood culture-confirmed typhoid fever. In the intention-to-treat population, efficacy of Vi-TT was 78·3% (95% CI 66·3-86·1), and 163 (129-222) children needed to be vaccinated to prevent one case. Efficacies by age group were 70·6% (6·4-93·0) for children aged 9 months to 2 years; 79·6% (45·8-93·9) for children aged 2-4 years; and 79·3% (63·5-89·0) for children aged 5-12 years., Interpretation: A single dose of Vi-TT is durably efficacious for at least 4 years among children aged 9 months to 12 years and shows efficacy in all age groups, including children younger than 2 years. These results support current WHO recommendations in typhoid-endemic areas for mass campaigns among children aged 9 months to 15 years, followed by routine introduction in the first 2 years of life., Funding: Bill & Melinda Gates Foundation., Competing Interests: Declaration of interests YL, SD, LPJ, MBL, and KMN receive funding from the TyVAC grant (grant number OPP1151153). KMN is a voting member of the WHO Strategic Advisory Group of Experts on Immunization (SAGE). RSH is a UK National Institute for Health and Care Research Senior Investigator. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Human infections with the avian influenza A(H7N9) virus were first reported in China in 2013 and continued to occur in annual waves. In the 2016/2017 fifth wave, Yangtze River Delta (YRD) lineage viruses, which differed antigenically from those of earlier waves, predominated., Methods: In this phase 2 double-blinded trial we randomized 720 adults ≥ 19 years of age to receive two injections of a YRD lineage inactivated A/Hong Kong/125/2017 fifth-wave H7N9 vaccine, given 21 days apart, at doses of 3.75, 7.5, and 15 µg of hemagglutinin (HA) with AS03A adjuvant and at doses of 15 and 45 µg of HA without adjuvant., Results: Two doses of adjuvanted vaccine were required to induce HA inhibition (HI) antibody titers ≥ 40 in most participants. After two doses of the 15 µg H7N9 formulation, given with or without AS03 adjuvant, the proportion achieving a HI titer ≥ 40 against the vaccine strain at 21 days after the second vaccination was 65 % (95 % CI, 57 %-73 %) and 0 % (95 % CI, 0 %-4%), respectively. Among those who received two doses of the 15 µg adjuvanted formulation the proportion with HI titer ≥ 40 at 21 days after the second vaccination was 76 % (95 % CI, 66 %-84 %) in those 19-64 years of age and 49 % (95 % CI, 37 %-62 %) in those ≥ 65 years of age. Responses to the adjuvanted vaccine formulations did not vary by HA content. Antibody responses declined over time and responses against drifted H7N9 strains were diminished. Overall, the vaccines were well tolerated but, as expected, adjuvanted vaccines were associated with more frequent solicited systemic and local adverse events., Conclusions: AS03 adjuvant improved the immune responses to an inactivated fifth-wave H7N9 influenza vaccine, particularly in younger adults, but invoked lower responses to drifted H7N9 strains. These findings may inform future influenza pandemic preparedness strategies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [LAJ reports funding support to her institution from Pfizer for the conduct of a clinical trial of an investigational influenza vaccine. NGR is a paid safety consultant for ICON and EMMES, serves on the advisory boards for GSK, Moderna, Sanofi, and Seqirus and her institution received funds for the conduct of research from Sanofi, Lilly, Merck, Quidel, and Pfizer. MJM reported potential competing interests: laboratory research and clinical trials contract funding with Lilly, Pfizer, and Sanofi; personal fees for Scientific Advisory Board service from Merck, Meissa Vaccines, Inc. and Pfizer. EBW has received funding support from Pfizer, Moderna, Sequiris, Najit Technologies Inc, and Clinetic for the conduct of clinical trials and clinical research and has served as an advisor to Vaxcyte and consultant to ILiAD biotechnologies. CAR.’s institution has received funds to conduct clinical research unrelated to this manuscript from BioFire Inc, GSK, MedImmune, Micron, Janssen, Merck, Moderna, Novavax, PaxVax, Pfizer, Regeneron, Sanofi-Pasteur. She is co-inventor of patented RSV vaccine technology unrelated to this manuscript, which has been licensed to Meissa Vaccines, Inc.]., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Typhoid fever is an invasive bacterial disease associated with bloodstream infection that causes a high burden of disease in Africa and Asia. Typhoid primarily affects individuals ranging from infants through to young adults. The causative organism, Salmonella enterica subsp. enterica serovar Typhi is transmitted via the faecal-oral route, crossing the intestinal epithelium and disseminating to systemic and intracellular sites, causing an undifferentiated febrile illness. Blood culture remains the practical reference standard for diagnosis of typhoid fever, where culture testing is available, but novel diagnostic modalities are an important priority under investigation. Since 2017, remarkable progress has been made in defining the global burden of both typhoid fever and antimicrobial resistance; in understanding disease pathogenesis and immunological protection through the use of controlled human infection; and in advancing effective vaccination programmes through strategic multipartner collaboration and targeted clinical trials in multiple high-incidence priority settings. This Primer thus offers a timely update of progress and perspective on future priorities for the global scientific community., (© 2023. Springer Nature Limited.)

Policymakers often rely on impact and cost-effectiveness evaluations to inform decisions about the introduction of health interventions in low- and middle-income countries (LMICs); however, cost-effectiveness results for the same health intervention can differ by the choice of parameter inputs, modelling assumptions, and geography. Anticipating the near-term availability of new respiratory syncytial virus (RSV) prevention products, WHO convened a two-day virtual consultation in April 2022 with stakeholder groups and global experts in health economics, epidemiology, and vaccine implementation. The objective was to review methods, parameterization, and results of existing cost-effectiveness analyses for RSV prevention in LMICs; identify the most influential inputs and data limitations; and recommend and prioritize future data gathering and research to improve RSV prevention impact estimates in LMICs. Epidemiological parameters identified as both influential and uncertain were those associated with RSV hospitalization and death, specifically setting-specific hospitalization rates and RSV-attributable death rates. Influential economic parameters included product price, delivery costs, willingness-to-pay for health on the part of potential donors, and the cost of RSV-associated hospitalization. Some of the influential parameters identified at this meeting should be more precisely measured by further research. Other influential economic parameters that are highly uncertain may not be resolved, and it is appropriate to use sensitivity analyses to explore these within cost-effectiveness evaluations. This report highlights the presentations and major discussions of the meeting., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Meagan C. Fitzpatrick: received grants to her institution from the National Institutes of Health, National Science Foundation, World Health Organization, and Bill & Melinda Gates Foundation; consulting fees from Sanofi Pasteur and The Commonwealth Fund. Rachel S. Laufer: none to declare. Ranju Baral: none to declare. Amanda Driscoll: none to declare. Danny Feikin : none to declare. Jessica A. Fleming: none to declare. Mark Jit: Mark Jit is an unpaid member of the Respiratory Syncytial Virus Consortium in Europe (RESCEU) and Preparing for RSV Immunisation and Surveillance in Europe (PROMISE). RESCEU and PROMISE have received funding from the Innovative Medicines Initiative 2 Joint Undertaking. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and the European Federation of Pharmaceutical Industries and Associations. Neither MJ nor his research group has received any forms of pecuniary or other support from the pharmaceutical industry. Sonnie Kim: none to declare. Mihaly Koltai: none to declare. You Li: Grants to his institutions from Wellcome Trust and GSK; personal fees from Pfizer, all outside the submitted work. Xiao Li: none to declare. Harish Nair: Received funding from Innovative Medicines Initiative, National Institute of Health Research, Pfizer, and Icosavax; Consultancies from Sanofi, Pfizer, GSK, MSD, ReViral, Icosavax, Astra Zeneca, and Abbvie all outside submitted work. Kathleen M. Neuzil: Is a member of the WHO Strategic Advisory Group of Experts on Immunization. Clint Pecenka: none to declare. Erin Sparrow: none to declare. Padmini Srikantiah: none to declare. Justin R. Ortiz: Grants to his institution from the National Science Foundation, Bill & Melinda Gates Foundation, Pfizer, NIH, and World Health Organization; consulting fees from Putnam and GSK; and participation on advisory boards for Pfizer, Seqirus, and Moderna, all outside the submitted work]., (Copyright © 2023. Published by Elsevier Ltd.)

Background: COVID-19 vaccines with alternative strain compositions are needed to provide broad protection against newly emergent SARS-CoV-2 variants of concern. This study aimed to describe the clinical efficacy and safety of a bivalent SARS-CoV-2 recombinant protein vaccine as a two-injection primary series during a period of circulation of the omicron (B.1.1.529) variant., Methods: We conducted a phase 3, parallel, randomised, modified double-blind, placebo-controlled trial in adults aged 18 years or older at 54 clinical research centres in eight countries (Colombia, Ghana, India, Kenya, Mexico, Nepal, Uganda, and Ukraine). Participants were recruited from the community and randomly assigned (1:1) by use of an interactive response technology system to receive two intramuscular 0·5 mL injections, 21 days apart, of the bivalent vaccine (5 μg of ancestral [D614] and 5 μg of beta [B.1.351] variant spike protein, with AS03 adjuvant) or placebo (0·9% normal saline). All participants, outcome assessors, and laboratory staff performing assays were masked to group assignments; those involved in the preparation and administration of the vaccines were unmasked. Participants were stratified by age (18-59 years and ≥60 years) and baseline SARS-CoV-2 rapid serodiagnostic test positivity. Symptomatic COVID-19 was defined as laboratory-confirmed (via nucleic acid amplification test or PCR test) COVID-19 with COVID-19-like illness symptoms. The primary efficacy endpoint was the clinical efficacy of the bivalent vaccine for prevention of symptomatic COVID-19 at least 14 days after the second injection (dose 2). Safety was assessed in all participants receiving at least one injection of the study vaccine or placebo. This trial is registered with ClinicalTrials.gov (NCT04904549) and is closed to recruitment., Findings: Between Oct 19, 2021, and Feb 15, 2022, 13 002 participants were enrolled and randomly assigned to receive the first dose of the study vaccine (n=6512) or placebo (n=6490). 12 924 participants (6472 in the vaccine group and 6452 in the placebo group) received at least one study injection, of whom 7542 (58·4%) were male and 9693 (75·0%) were SARS-CoV-2 non-naive. Of these 12 924 participants, 11 543 (89·3%) received both study injections (5788 in the vaccine group and 5755 in the placebo group). The efficacy-evaluable population after dose 2 comprised 11 416 participants (5736 in the vaccine group and 5680 in the placebo group). The median duration of follow-up was 85 days (IQR 50-95) after dose 1 and 58 days (29-70) after dose 2. 121 symptomatic COVID-19 cases were reported at least 14 days after dose 2 (32 in the vaccine group and 89 in the placebo group), with an overall vaccine efficacy of 64·7% (95% CI 46·6 to 77·2). Vaccine efficacy against symptomatic COVID-19 was 75·1% (95% CI 56·3 to 86·6) in SARS-CoV-2 non-naive participants and 30·9% (-39·3 to 66·7) in SARS-CoV-2-naive participants. Viral genome sequencing identified the infecting strain in 68 (56·2%) of 121 cases (omicron [BA.1 and BA.2] in 63; delta in four; and both omicron and delta in one). Immediate unsolicited adverse events were reported by four (<0·1%) participants in the vaccine group and seven (0·1%) participants in the placebo group. Immediate unsolicited adverse reactions within 30 min after any injection were reported by four (<0·1%) participants in the vaccine group and six (<0·1%) participants in the placebo group. In the reactogenicity subset with available data, solicited reactions (solicited injection-site reactions and solicited systemic reactions) within 7 days after any injection occurred in 1398 (57·8%) of 2420 vaccine recipients and 983 (40·9%) of 2403 placebo recipients. Grade 3 solicited reactions were reported by 196 (8·1%; 95% CI 7·0 to 9·3) of 2420 vaccine recipients and 118 (4·9%; 4·1 to 5·9) of 2403 placebo recipients within 7 days after any injection, with comparable frequencies after dose 1 and dose 2 in the vaccine group. At least one serious adverse event occurred in 30 (0·5%) participants in the vaccine group and 26 (0·4%) in the placebo group. The proportion of adverse events of special interest and deaths was less than 0·1% in both study groups. No adverse event of special interest, serious adverse event, or death was deemed to be treatment related. There were no reported cases of thrombosis with thrombocytopenia syndrome, myocarditis, pericarditis, Bell's Palsy, or Guillain-Barré syndrome, or other immune-mediated diseases., Interpretation: The bivalent variant vaccine conferred heterologous protection against symptomatic SARS-CoV-2 infection in the epidemiological context of the circulating contemporary omicron variant. These findings suggest that vaccines developed with an antigen from a non-predominant strain could confer cross-protection against newly emergent SARS-CoV-2 variants, although further investigation is warranted., Funding: Sanofi, US Biomedical Advanced Research and Development Authority, and the US National Institute of Allergy and Infectious Diseases., Competing Interests: Declaration of interests GHD, MIB, BF, M-HG, MC, JA, CAD, RMC, SG, SSr, and SSa are Sanofi employees. MIB, BF, M-HG, JA, CAD, RMC, and SSr hold stock or stock options in Sanofi. SG, RMC, and SSr hold patents pending on a COVID-19 vaccine. The Center for Vaccine Development and Global Health (CVD) receives grants from Pfizer to conduct clinical trials of COVID-19 vaccines. KMN receives no salary support for this grant. KMN receives grants from the US National Institutes of Health (NIH) to participate in overall organisation of COVID-19 vaccine trials and for participation in vaccine trials. RMC has received institutional funding from the Biomedical Advanced Research and Development Authority (BARDA) for the present study; has received support for attending meetings or travel, from Sanofi; and holds patents planned, issued, or pending from Sanofi. M-HG has received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Sanofi. NR has received institutional funding from the NIH; and institutional grants or contracts from Merck, Sanofi, Quidel, Pfizer, and Lilly. SRW has received institutional funding from Sanofi and the National Institute of Allergy and Infectious Diseases (NIAID) and NIH; and institutional grants or contracts from Janssen Vaccines/Johnson & Johnson, Moderna Tx, Vir Biotechnology, and Worcester HIV Vaccine; has participated on data safety monitoring or advisory boards for Janssen Vaccines/Johnson & Johnson; and his spouse holds stocks and stock options in Regeneron Pharmaceuticals. NG has received institutional funding from Sanofi, GSK, and the NIAID and NIH; and is in receipt of grants or contracts from the NIH, NIAID, and the Division of AIDS (DAIDS). MA and TT are employees of NIAID, which funded aspects of the current study. LS, MAC, and MK are employees of GSK and own shares in the GSK group of companies. MJ and JJK have received institutional support from Sanofi and NIAID and NIH with respect to this study. MLR has received institutional support or contracts for the present manuscript from Walter Reed Army Institute of Research, Ingenuity Pathway Analysis, and the US Medical Research and Development Command. SSa was a Sanofi employee at the time of study conduct; and holds patents planned, issued, or pending on COVID-19 vaccines. LC has received grant funding from the NIAID/NIH. AC, KPA, ASB, TB, DD, MK-J, HK, RM, NLM, HR, SMVM, FS, JT, and TAW, declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection., Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7-15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures., Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05-0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01-0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease., Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection., Funding: National Institutes of Health., Competing Interests: Declaration of interests YiH, CY, TCSM, RMM, HMES, BG, GEG, PBG, JGK, LC, and DF declare no conflicts of interest. AMR declares unrelated grants or contracts from NIAID, I4kids, Society to Improve Diagnosis in Medicine, Beckwith Clinical Innovation Award, CTSI COVID-19 Pilot Award; unrelated consulting fees from Pfizer; unrelated support for attending meetings/travel from IDweek (2023); and an unrelated unpaid leadership role as the medical director of Human Milk Science Institute and Biobank. MBL declares unrelated grants or contracts from NIH VTEU paid to their institution. CaAR declares unrelated grants or contracts paid to their institution from Novavax and Moderna. ChAR declares unrelated grants or contracts paid to their institution from BioFire, Inc, GSK, Merck, Micron, MedImmune, Novavax, PaxVax, Regeneron, Pfizer, Sanofi-Pasteur, Janssen, Moderna, NIH, and CDC; unrelated royalties or licenses from Meissa Vaccines, Inc; and unrelated patent interests for “RSV Live-Attenuated Vaccine Candidates with Deleted G-Protein Mucin Domains” and “Chimeric RSV, Immunogenic, Compositions, and Methods of Use”. LRB declares unrelated grants or contracts paid to their institution from NIH/Harvard Medical School and Wellcome Trust/Gates Foundation; unrelated participation on a Data Safety Monitoring Board or Advisory Board for NIAID and FDA; and unrelated involvement in HIV and SARS-CoV-2 vaccine clinical trials conducted in collaboration with the NIH, HIV Vaccine Trials Network (HVTN), Covid Vaccine Prevention Network (CoVPN), International AIDS Vaccine Initiative (IAVI), Crucell/Janssen, Moderna, Military HIV Research Program (MHRP), the Gates Foundation, and Harvard Medical School. CLG declares unrelated grants or contracts paid to their institution from NIH. HEJ declares unrelated grants or contracts paid to their institution from NIH; and unrelated participation in multiple NIH-convened DSMBs. YuH declares unrelated grants or contracts paid to their institution from WHO and unrelated participation (with payment) on a Data Safety Monitoring Board or Advisory Board for WHV. BL is an employee of Moderna, Inc. IH is an employee of AstraZeneca and declares unrelated stock options held in AstraZeneca. FS is an employee of Janssen and declares unrelated stock received as compensation for past employment with GlaxoSmithKline. LMD is an employee of Novavax, Inc. KMN declares unrelated grants or contracts from Pfizer (no salary support) and NIH. PAG declares unrelated grants or contracts from NIH and patent interests for “Human monoclonal antibodies to SARS-COV-2 and use thereof”. SRW declares unrelated grants or contracts from Sanofi Pasteur, Moderna, Vir Biotechnology, Worcester HIV Vaccine, Pfizer, and Janssen Vaccines/Johnson & Johnson paid to their institution; unrelated support for attending meetings and/or travel from Sasnofi Pasteur; unrelated participation on a Data Safety Monitoring Board or Advisory Board for Janssen Vaccines/Johnson & Johnson; and that their spouse is an employee that holds stock/stock options at Regeneron Pharmaceuticals. KLK declares unrelated grants or contracts from NIAID. The CoVPN was funded by the NIH., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The COVE trial randomized participants to receive two doses of mRNA-1273 vaccine or placebo on Days 1 and 29 (D1, D29). Anti-SARS-CoV-2 Spike IgG binding antibodies (bAbs), anti-receptor binding domain IgG bAbs, 50% inhibitory dilution neutralizing antibody (nAb) titers, and 80% inhibitory dilution nAb titers were measured at D29 and D57. We assessed these markers as correlates of protection (CoPs) against COVID-19 using stochastic interventional vaccine efficacy (SVE) analysis and principal surrogate (PS) analysis, frameworks not used in our previous COVE immune correlates analyses. By SVE analysis, hypothetical shifts of the D57 Spike IgG distribution from a geometric mean concentration (GMC) of 2737 binding antibody units (BAU)/mL (estimated vaccine efficacy (VE): 92.9% (95% CI: 91.7%, 93.9%)) to 274 BAU/mL or to 27,368 BAU/mL resulted in an overall estimated VE of 84.2% (79.0%, 88.1%) and 97.6% (97.4%, 97.7%), respectively. By binary marker PS analysis of Low and High subgroups (cut-point: 2094 BAU/mL), the ignorance interval (IGI) and estimated uncertainty interval (EUI) for VE were [85%, 90%] and (78%, 93%) for Low compared to [95%, 96%] and (92%, 97%) for High. By continuous marker PS analysis, the IGI and 95% EUI for VE at the 2.5th percentile (519.4 BAU/mL) vs. at the 97.5th percentile (9262.9 BAU/mL) of D57 Spike IgG concentration were [92.6%, 93.4%] and (89.2%, 95.7%) vs. [94.3%, 94.6%] and (89.7%, 97.0%). Results were similar for other D29 and D57 markers. Thus, the SVE and PS analyses additionally support all four markers at both time points as CoPs.

We assessed anti-Vi IgG/IgA responses to typhoid conjugate vaccine (TCV) in children enrolled in a double-blind randomized controlled, phase 2 trial in Burkina Faso. Anti-Vi IgG seroconversion and anti-Vi IgA titers were higher in TCV than control recipients at 30-35 months post-vaccination. TCV induces durable immunity in Burkinabe children vaccinated at 15 months., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society.)

Background: The literature on first generation COVID-19 vaccines show they were less effective against new SARS-CoV-2 variants of concern including Omicron (BA.1, BA.2, BA.4 and BA.5 subvariants). New vaccines developed against variant strains may provide cross-protection against emerging variants when used as boosters and facilitate vaccination across a range of countries, healthcare settings and populations. However, there are no data on such vaccines when used as a primary series., Methods: A global Phase 3, multi-stage efficacy study (NCT04904549) among adults (≥18 years) was conducted in 53 research centres in eight countries (United States, Honduras, Japan, Colombia, Kenya, India, Ghana, Nepal). Participants were randomized 1:1 to receive two intramuscular injections of a monovalent SARS-CoV-2 recombinant protein vaccine with AS03-adjuvant (10 μg of the spike (S) protein from the ancestral D614 strain) or placebo on Day 1 (D01) and Day 22 (D22). The primary efficacy endpoint was prevention of virologically confirmed SARS-CoV-2 infection with symptoms of COVID-19-like illness (CLI) ≥14 days after the second injection (post-dose 2 [PD2]) in participants who were SARS-CoV-2 naïve on D01 + D22. Safety and reactogenicity were also evaluated., Findings: Between May 26 and November 7, 2021, 10,114 participants received ≥1 study injection, and 9441 participants received both injections. 2108 (20.8%) participants were SARS-CoV-2 naïve at D01 and D22. The primary endpoint was analysed in a subset of the full analysis set (the modified full analysis set PD2 [mFAS-PD2], excluding participants who did not complete the vaccination schedule or received vaccination despite meeting one of the contraindication criteria, had onset of symptomatic COVID-19 between the first injection and before 14 days after the second injection, or participants who discontinued before 14 days after the second injection [n = 9377; vaccine, n = 4702; placebo, n = 4675]). Data were available for 2051 SARS-CoV-2 naïve and 7159 non-naïve participants. At the cut-off date (January 28, 2022), symptomatic COVID-19 was reported in 169 naïve participants (vaccine, n = 81; placebo, n = 88) ≥14 days PD2, with a vaccine efficacy (VE) of 15.3% (95% CI, -15.8; 38.2). VE regardless of D01/D22 serostatus was 32.9% (95% CI, 15.3; 47.0) and VE in non-naïve participants was 52.7% (95% CI, 31.2; 67.9). Viral genome sequencing was performed up to the data cut-off point and identified the infecting strain in 99/169 adjudicated cases in the PD2 naïve population (Delta [25], Omicron [72], other variants [3], one participant had infection with both Delta and Omicron variants and has been included in the totals for both Delta and Omicron). The vaccine was well-tolerated with an acceptable safety profile., Interpretation: In the context of changing circulating viral variants, it is challenging to induce protection in naïve individuals with a two-dose priming schedule based on the parental D614 strain. However, while the primary endpoint of this trial was not met, the results show that a monovalent D614 vaccine can still be of value in individuals previously exposed to SARS-CoV-2., Funding: This study was funded in whole or in part by Sanofi and by federal funds from the Biomedical Advanced Research and Development Authority, part of the office of the Administration for Strategic Preparedness and Response at the U.S. Department of Health and Human Services under contract number HHSO100201600005I, and in collaboration with the U.S. Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense under contract number W15QKN-16-9-1002. The views presented here are those of the authors and do not purport to represent those of the Department of the Army, the Department of Health and Human Services, or the U.S. government., Competing Interests: GHD, JA, MIB, MC, M-HG, JA, CAD, RMC, MC and SSa are Sanofi employees. JA, MIB, M-HG, JA, CAD, RMC, MC, CAD, SSr and SSa hold stock or stock options in Sanofi. SSr and SSa are the named inventors on a patent associated with the vaccine reported in this manuscript. RMC has received institutional funding from BARDA for the present study; has received support for attending meetings and/or travel from Sanofi; and holds patents planned, issued or pending from Sanofi. NR has received institutional funding from the National Institutes of Health; and institutional grants or contracts from Merck, Sanofi, Quidel, Pfizer and Lilly. SRW has received institutional funding from Sanofi and the National Institute of Allergy and Infectious Diseases/National Institutes of Health; and institutional grants or contracts from Janssen Vaccines/Johnson & Johnson, Moderna Tx, Pfizer, Vir Biotechnology and Worcester HIV Vaccine; has participated on data safety monitoring or advisory boards for Janssen Vaccines/Johnson & Johnson; and his spouse holds stock/stock options in Regeneron Pharmaceuticals. NG has received institutional grants from the National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID). LS, MAC and MK are employees of the GSK group of companies and own shares in the GSK group of companies. MJ and JJK have received institutional support from Sanofi and the NIAID/NIH with respect to this study. MLR has received institutional support/contracts for the present manuscript from WRAIR IPA and the US Medical Research and Development Command. MA, and MKJ are employees of the NIAID, which funded aspects of the current study; The NIAID provides grant funding to the HIV Vaccine Trials Network (HVTN) Leadership and Operations Center (UM1 AI 68614HVTN), the Statistics and Data Management Center (UM1 AI 68635), the HVTN Laboratory Center (UM1 AI 68618), the HIV Prevention Trials Network Leadership and Operations Center (UM1 AI 68619), the AIDS Clinical Trials Group Leadership and Operations Center (UM1 AI 68636), and the Infectious Diseases Clinical Research Consortium leadership group 5 (UM1 AI 148684-03). One of the sites in Kenya in this study received funding from NIAID. LC has received grant funding from the NIAD/NIH. The Center for Vaccine Development and Global Health (CVD) receives grants from Pfizer to conduct clinical trials of COVID-19 vaccines: KMN receives no salary support for this grant. KMN receives grants from NIH to participate in overall organization of COVID vaccine trials and for participation in vaccine trials. ASB has received honorarium for the conduct of this trial as Principal Investigator from Sanofi Healthcare India Private Limited. TT, SK, BF, AC, KPA, TB, RM, NLM, HR, FS, JT, SG, KS, AU and RS have no interests to declare., (© 2023 The Author(s).)

Vaccine protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection wanes over time, requiring updated boosters. In a phase 2, open-label, randomized clinical trial with sequentially enrolled stages at 22 US sites, we assessed safety and immunogenicity of a second boost with monovalent or bivalent variant vaccines from mRNA and protein-based platforms targeting wild-type, Beta, Delta and Omicron BA.1 spike antigens. The primary outcome was pseudovirus neutralization titers at 50% inhibitory dilution (ID 50 titers) with 95% confidence intervals against different SARS-CoV-2 strains. The secondary outcome assessed safety by solicited local and systemic adverse events (AEs), unsolicited AEs, serious AEs and AEs of special interest. Boosting with prototype/wild-type vaccines produced numerically lower ID 50 titers than any variant-containing vaccine against all variants. Conversely, boosting with a variant vaccine excluding prototype was not associated with decreased neutralization against D614G. Omicron BA.1 or Beta monovalent vaccines were nearly equivalent to Omicron BA.1 + prototype or Beta + prototype bivalent vaccines for neutralization of Beta, Omicron BA.1 and Omicron BA.4/5, although they were lower for contemporaneous Omicron subvariants. Safety was similar across arms and stages and comparable to previous reports. Our study shows that updated vaccines targeting Beta or Omicron BA.1 provide broadly crossprotective neutralizing antibody responses against diverse SARS-CoV-2 variants without sacrificing immunity to the ancestral strain. ClinicalTrials.gov registration: NCT05289037 ., (© 2023. The Author(s).)

The immune response to COVID-19 booster vaccinations during pregnancy for mothers and their newborns and the functional response of vaccine-induced antibodies against Omicron variants are not well characterized. We conducted a prospective, multicenter cohort study of participants vaccinated during pregnancy with primary or booster mRNA COVID-19 vaccines from July 2021 to January 2022 at 9 academic sites. We determined SARS-CoV-2 binding and live virus and pseudovirus neutralizing antibody (nAb) titers pre- and post-vaccination, and at delivery for both maternal and infant participants. Immune responses to ancestral and Omicron BA.1 SARS-CoV-2 strains were compared between primary and booster vaccine recipients in maternal sera at delivery and in cord blood, after adjusting for days since last vaccination. A total of 240 participants received either Pfizer or Moderna mRNA vaccine during pregnancy (primary 2-dose series: 167; booster dose: 73). Booster vaccination resulted in significantly higher binding and nAb titers, including to the Omicron BA.1 variant, in maternal serum at delivery and in cord blood compared to a primary 2-dose series (range 0.44-0.88 log 10 higher, p < 0.0001 for all comparisons). Live virus nAb to Omicron BA.1 were present at delivery in 9 % (GMT ID50 12.7) of Pfizer and 22 % (GMT ID50 14.7) of Moderna primary series recipients, and in 73 % (GMT ID50 60.2) of mRNA boosted participants (p < 0.0001), although titers were significantly lower than to the D614G strain. Transplacental antibody transfer was efficient for all regimens with median transfer ratio range: 1.55-1.77 for IgG, 1.00-1.78 for live virus nAb and 1.79-2.36 for pseudovirus nAb. COVID-19 mRNA vaccination during pregnancy elicited robust immune responses in mothers and efficient transplacental antibody transfer to the newborn. A booster dose during pregnancy significantly increased maternal and cord blood binding and neutralizing antibody levels, including against Omicron BA.1. Findings support the use of a booster dose of COVID-19 vaccine during pregnancy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: F.M.M. is an investigator of pediatric studies of COVID-19 vaccines for Pfizer and for a pediatric remdesivir study conducted by Gilead Sciences, Inc; serves as investigator on projects supported by an NIH contract for a Vaccine Treatment and Evaluation Unit (VTEU), serves as member of the Data Safety monitoring Board (DSMB) for clinical trials conducted by Pfizer, Moderna, Meissa Vaccines, Virometix, and the NIH; and is a member of the American Academy of Pediatrics Section of Infectious Diseases (SOID), the Immunization Expert Group of the American College of Obstetrics and Gynecology (ACOG), and was co-Chair of the COVAX-CEPI Maternal Immunization Working Group. K.M.N. is a member of the World Health Organization (WHO) Strategic Advisory Group of Experts on Immunization, serves as co-investigator on an NIH contract for a Vaccine Treatment and Evaluation Unit (VTEU), serves as Co-Chair of the NIH COVID Prevention Network (CoVPN), and served as an investigator for Phase I/II Pfizer COVID-19 vaccine grant, with a grant to the institution, but no salary support. M.J.M. conducts laboratory research and clinical trials with contract funding for vaccines or MABs vs SARS-CoV-2 with Lilly, Pfizer, and Sanofi and receives personal fees for Scientific Advisory Board service from Merck, Meissa Vaccines, Inc. and Pfizer. M.S.S. served as an advisor for Moderna (ended December 2021) and is currently serving as an advisor for Ocugen, Inc. B.A.R. currently holds a position on a DSMB for clinical trials at Gilead Sciences, Inc. R.C.B. at Cincinnati Children’s Hospital receives research grant support for clinical trials from PATH, Astra Zeneca and Pfizer on which she serves as co-investigator. B.B. owns shares in HDT Bio Corp. J.S.G. receives research funds from NIH for Moderna KidCOVE study. R.M.N. is a paid advisor to Gilead and an investigator on NIH-funded trials of Moderna, Pfizer and Janssen vaccines. J.R-K is a medical speaker for Abbott Nutrition with the UIC team. A.R.F. holds research grants from Pfizer, Janssen, Merck, Cyanvac, Biofire Diagnostics and serves on the DSMB for Novavax. N.R. receives funds to conduct industry trials from Pfizer, Merck, and Sanofi-Pasteur and serves as a safety consultant for EMMES and ICON. R.W.F. Jr., MD has received funds to conduct industry trials from Pfizer, Moderna and Astra Zeneca, serves on advisory boards for Merck, Sanofi-Pasteur, Johnson and Johnson and Seqirus and serves on an ICON-sponsored DSMB for a C difficile study., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: We evaluated the associations between baseline influenza virus-specific hemagglutination inhibition (HAI) and microneutralization (MN) titers and subsequent symptomatic influenza virus infection in a controlled human infection study., Methods: We inoculated unvaccinated healthy adults aged 18-49 years with an influenza A/California/04/2009/H1N1pdm-like virus (NCT04044352). We collected serial safety labs, serum for HAI and MN, and nasopharyngeal swabs for reverse-transcription polymerase chain reaction (RT-PCR) testing. Analyses used the putative seroprotective titer of ≥40 for HAI and MN. The primary clinical outcome was mild-to-moderate influenza disease (MMID), defined as ≥1 postchallenge positive qualitative RT-PCR test with a qualifying symptom/clinical finding., Results: Of 76 participants given influenza virus challenge, 54 (71.1%) experienced MMID. Clinical illness was generally very mild. MMID attack rates among participants with baseline titers ≥40 by HAI and MN were 64.9% and 67.9%, respectively, while MMID attack rates among participants with baseline titers <40 by HAI and MN were 76.9% and 78.3%, respectively. The estimated odds of developing MMID decreased by 19% (odds ratio, 0.81 [95% confidence interval, .62-1.06]; P = .126) for every 2-fold increase in baseline HAI. There were no significant adverse events., Conclusions: We achieved a 71.1% attack rate of MMID. High baseline HAI and MN were associated with protection from illness. Clinical Trials Registration. NCT04044352., Competing Interests: Potential conflicts of interest. J. R. O. reports grants to his institution from the National Science Foundation, Bill & Melinda Gates Foundation, Pfizer, NIH, and World Health Organization; consulting fees from Putnam; and participation on advisory boards for Pfizer, Seqirus, and Moderna, all outside the submitted work. D. I. B. reports consulting fees from Rational Vaccines and participation on an advisory board with Moderna and Dynavax, outside the submitted work. C. W. W. reports grants to his institution from Janssen and AstraZeneca, outside the submitted work. M. T. M. reports grants to his institution from NIH, outside the submitted work. R. W. F. reports grants to his institution from Pfizer, outside the submitted work, and clinical trial support from Pfizer. E. W. reports grants to his institution from Clinetic, Moderna, Pfizer, Seqirus, and Iliad Biotechnologies; consulting fees from Iliad Biotechnologies; and participation on the Vaxcyte advisory board. W. A. K. reports grants to her institution from Leidos, outside the submitted work; clinical trial support from Pfizer; subcontract from Leidos; and advisory board participation with the NIH. N. R. reports grants to her institution from Merck, Sanofi Pasteur, Quidel, Pfizer, and Lilly, outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Questions remain regarding the effect of baseline host and exposure factors on vaccine efficacy (VE) across pathogens and vaccine platforms. We report placebo-controlled data from four Phase 3 COVID-19 trials during the early period of the pandemic. This was a cross-protocol analysis of four randomized, placebo-controlled efficacy trials (Moderna/mRNA1273, AstraZeneca/AZD1222, Janssen/Ad26.COV2.S, and Novavax/NVX-CoV2373) using a harmonized design. Trials were conducted in the United States and international sites in adults ≥ 18 years of age. VE was assessed for symptomatic and severe COVID-19. We analyzed 114,480 participants from both placebo and vaccine arms, enrolled July 2020 to February 2021, with follow up through July 2021. VE against symptomatic COVID-19 showed little heterogeneity across baseline socio-demographic, clinical or exposure characteristics, in either univariate or multivariate analysis, regardless of vaccine platform. Similarly, VE against severe COVID-19 in the single trial (Janssen) with sufficient endpoints for analysis showed little evidence of heterogeneity. COVID-19 VE is not influenced by baseline host or exposure characteristics across efficacy trials of different vaccine platforms and countries when well matched to circulating virus strains. This supports use of these vaccines, regardless of platform type, as effective tools in the near term for reducing symptomatic and severe COVID-19, particularly for older individuals and those with common co-morbidities during major variant shifts. Clinical trial registration numbers: NCT04470427, NCT04516746, NCT04505722, and NCT04611802., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Brett Leav reports a relationship with Moderna Inc that includes: employment. Jacqueline Miller reports a relationship with Moderna Inc that includes: employment. Kathryn Shoemaker reports a relationship with AstraZeneca R&D Gaithersburg that includes: employment and equity or stocks. An Vandenbosch reports a relationship with Janssen Pharmaceuticals Inc that includes: employment. Jerald Sadoff reports a relationship with Janssen Pharmaceuticals Inc that includes: employment. Wayne Woo reports a relationship with Novavax Inc that includes: employment. Iksung Cho reports a relationship with Novavax Inc that includes: employment. Lisa M. Dunkle reports a relationship with Novavax Inc that includes: employment. Peter Gilbert reports a relationship with Janssen Pharmaceuticals Inc that includes: consulting or advisory. Hana M. El Sahly reports a relationship with Gilead Sciences Inc that includes: funding grants. Hana M. El Sahly reports a relationship with Janssen Global Services LLC that includes: funding grants. Hana M. El Sahly reports a relationship with Merck & Co Inc that includes: funding grants. Hana M. El Sahly reports a relationship with Sanofi Pasteur Inc that includes: funding grants. Kathleen M. Neuzil reports a relationship with Pfizer Inc that includes: funding grants. Ann R. Falsey reports a relationship with Biofire Diagnostics Inc that includes: funding grants. Ann R. Falsey reports a relationship with Janssen Biotech Inc that includes: funding grants. Ann R. Falsey reports a relationship with Merck & Co Inc that includes: funding grants. Ann R. Falsey reports a relationship with Pfizer Inc that includes: funding grants. Ann R. Falsey reports a relationship with Novavax Inc that includes: consulting or advisory., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

As part of a multicenter study evaluating homologous and heterologous COVID-19 booster vaccines, we assessed the magnitude, breadth, and short-term durability of binding and pseudovirus-neutralizing antibody (PsVNA) responses following a single booster dose of NVX-CoV2373 in adults primed with either Ad26.COV2.S, mRNA-1273, or BNT162b2 vaccines. NVX-CoV2373 as a heterologous booster was immunogenic and associated with no safety concerns through Day 91. Fold-rises in PsVNA titers from baseline (Day 1) to Day 29 were highest for prototypic D614G variant and lowest for more recent Omicron sub-lineages BQ.1.1 and XBB.1. Peak humoral responses against all SARS-CoV-2 variants were lower in those primed with Ad26.COV2.S than with mRNA vaccines. Prior SARS CoV-2 infection was associated with substantially higher baseline PsVNA titers, which remained elevated relative to previously uninfected participants through Day 91. These data support the use of heterologous protein-based booster vaccines as an acceptable alternative to mRNA or adenoviral-based COVID-19 booster vaccines. This trial was conducted under ClinicalTrials.gov: NCT04889209., (© 2023. The Author(s).)

Importance: Current data identifying COVID-19 risk factors lack standardized outcomes and insufficiently control for confounders., Objective: To identify risk factors associated with COVID-19, severe COVID-19, and SARS-CoV-2 infection., Design, Setting, and Participants: This secondary cross-protocol analysis included 4 multicenter, international, randomized, blinded, placebo-controlled, COVID-19 vaccine efficacy trials with harmonized protocols established by the COVID-19 Prevention Network. Individual-level data from participants randomized to receive placebo within each trial were combined and analyzed. Enrollment began July 2020 and the last data cutoff was in July 2021. Participants included adults in stable health, at risk for SARS-CoV-2, and assigned to the placebo group within each vaccine trial. Data were analyzed from April 2022 to February 2023., Exposures: Comorbid conditions, demographic factors, and SARS-CoV-2 exposure risk at the time of enrollment., Main Outcomes and Measures: Coprimary outcomes were COVID-19 and severe COVID-19. Multivariate Cox proportional regression models estimated adjusted hazard ratios (aHRs) and 95% CIs for baseline covariates, accounting for trial, region, and calendar time. Secondary outcomes included severe COVID-19 among people with COVID-19, subclinical SARS-CoV-2 infection, and SARS-CoV-2 infection., Results: A total of 57 692 participants (median [range] age, 51 [18-95] years; 11 720 participants [20.3%] aged ≥65 years; 31 058 participants [53.8%] assigned male at birth) were included. The analysis population included 3270 American Indian or Alaska Native participants (5.7%), 7849 Black or African American participants (13.6%), 17 678 Hispanic or Latino participants (30.6%), and 40 745 White participants (70.6%). Annualized incidence was 13.9% (95% CI, 13.3%-14.4%) for COVID-19 and 2.0% (95% CI, 1.8%-2.2%) for severe COVID-19. Factors associated with increased rates of COVID-19 included workplace exposure (high vs low: aHR, 1.35 [95% CI, 1.16-1.58]; medium vs low: aHR, 1.41 [95% CI, 1.21-1.65]; P < .001) and living condition risk (very high vs low risk: aHR, 1.41 [95% CI, 1.21-1.66]; medium vs low risk: aHR, 1.19 [95% CI, 1.08-1.32]; P < .001). Factors associated with decreased rates of COVID-19 included previous SARS-CoV-2 infection (aHR, 0.13 [95% CI, 0.09-0.19]; P < .001), age 65 years or older (aHR vs age <65 years, 0.57 [95% CI, 0.50-0.64]; P < .001) and Black or African American race (aHR vs White race, 0.78 [95% CI, 0.67-0.91]; P = .002). Factors associated with increased rates of severe COVID-19 included race (American Indian or Alaska Native vs White: aHR, 2.61 [95% CI, 1.85-3.69]; multiracial vs White: aHR, 2.19 [95% CI, 1.50-3.20]; P < .001), diabetes (aHR, 1.54 [95% CI, 1.14-2.08]; P = .005) and at least 2 comorbidities (aHR vs none, 1.39 [95% CI, 1.09-1.76]; P = .008). In analyses restricted to participants who contracted COVID-19, increased severe COVID-19 rates were associated with age 65 years or older (aHR vs <65 years, 1.75 [95% CI, 1.32-2.31]; P < .001), race (American Indian or Alaska Native vs White: aHR, 1.98 [95% CI, 1.38-2.83]; Black or African American vs White: aHR, 1.49 [95% CI, 1.03-2.14]; multiracial: aHR, 1.81 [95% CI, 1.21-2.69]; overall P = .001), body mass index (aHR per 1-unit increase, 1.03 [95% CI, 1.01-1.04]; P = .001), and diabetes (aHR, 1.85 [95% CI, 1.37-2.49]; P < .001). Previous SARS-CoV-2 infection was associated with decreased severe COVID-19 rates (aHR, 0.04 [95% CI, 0.01-0.14]; P < .001)., Conclusions and Relevance: In this secondary cross-protocol analysis of 4 randomized clinical trials, exposure and demographic factors had the strongest associations with outcomes; results could inform mitigation strategies for SARS-CoV-2 and viruses with comparable epidemiological characteristics.

Typhoid fever is a serious disease that disproportionately impacts children in low-resource settings in sub-Saharan Africa, South and Southeast Asia, and the Western Pacific. The prevalence of antimicrobial-resistant strains of S. Typhi continue to increase worldwide. Two safe, effective, and cost-effective typhoid conjugate vaccines (TCVs) are World Health Organization-prequalified for the prevention of typhoid fever in children as young as 6 months. Typhoid conjugate vaccines have proven effectiveness in preventing drug-resistant S. Typhi and have been deployed successfully in outbreak response and routine immunization scenarios. Broad and equitable distribution of TCVs is essential to combat the spread and potentially devastating consequences of typhoid fever. It is vital to empower decision-makers in typhoid-endemic countries to introduce TCVs and for leaders to embrace this critical tool to prevent typhoid fever, slow the spread of drug-resistant S. Typhi strains, promote health equity, and save lives., Competing Interests: Potential conflicts of interest. NF, LPJ, and KMN receive salary from the TyVAC grant from the Bill & Melinda Gates Foundation. KMN is a member of the World Health Organization Strategic Advisory Group of Experts on Immunization (SAGE). Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Typhoid intestinal perforation (TIP) remains the most serious complication of typhoid fever. In many countries, the diagnosis of TIP relies on intraoperative identification, as blood culture and pathology capacity remain limited. As a result, many cases of TIP may not be reported as typhoid. This study demonstrates the burden of TIP in sites in Burkina Faso, Democratic Republic of Congo (DRC), Ethiopia, Ghana, Madagascar, and Nigeria., Methods: Patients with clinical suspicion of nontraumatic intestinal perforation were enrolled and demographic details, clinical findings, surgical records, blood cultures, tissue biopsies, and peritoneal fluid were collected. Participants were then classified as having confirmed TIP, probable TIP, possible TIP, or clinical intestinal perforation based on surgical descriptions and cultures., Results: A total of 608 participants were investigated for nontraumatic intestinal perforation; 214 (35%) participants had surgically-confirmed TIP and 33 participants (5%) had culture-confirmed typhoid. The overall proportion of blood or surgical site Salmonella enterica subspecies enterica serovar Typhi positivity in surgically verified TIP cases was 10.3%. TIP was high in children aged 5-14 years in DRC, Ghana, and Nigeria. We provide evidence for correlation between monthly case counts of S. Typhi and the occurrence of intestinal perforation., Conclusions: Low S. Typhi culture positivity rates, as well as a lack of blood and tissue culture capability in many regions where typhoid remains endemic, significantly underestimate the true burden of typhoid fever. The occurrence of TIP may indicate underlying typhoid burden, particularly in countries with limited culture capability., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)