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Oral rotavirus vaccines have consistently proven to be less immunogenic among infants in developing countries. Discrepancies in the intestinal microbiota, including a greater burden of enteropathogens and an altered commensal community composition, may contribute to this trend by inhibiting the replication of vaccine viruses. To test this possibility, we performed a nested case–control study in Vellore, India, in which we compared the intestinal microbiota of infants who responded serologically or not after two doses of Rotarix delivered at 6 and 10 weeks of age as part of a clinical trial (CTRI/2012/05/002677). The prevalence of 40 bacterial, viral, and eukaryotic pathogen targets was assessed in pre-vaccination stool samples from 325 infants using singleplex real-time PCR on a Taqman array card (TAC). In a subset of 170 infants, we assessed bacterial microbiota composition by sequencing the 16S rRNA gene V4 region. Contrary to expectations, responders were more likely than non-responders to harbor ≥1 bacterial enteropathogen at dose 1 (26% [40/156] vs 13% [21/157] of infants with TAC results who completed the study per protocol; χ2, P = .006), although this was not apparent at dose 2 (24% [38/158] vs 23% [36/158]; P = .790). Rotavirus shedding after dose 1 was negatively correlated with the replication of co-administered oral poliovirus vaccine (OPV). We observed no consistent differences in composition or diversity of the 16S bacterial microbiota according to serological response, although rotavirus shedding was associated with slightly more bacterial taxa pre-vaccination. Overall, our findings demonstrate an inhibitory effect of co-administered OPV on the first dose of Rotarix, consistent with previous studies, but in the context of OPV co-administration we did not find a strong association between other components of the intestinal microbiota at the time of vaccination and Rotarix immunogenicity.

Pakistan is one of two countries in which poliovirus remains endemic. Considering the high number of children born every year, reaching and vaccinating new birth cohorts by improving routine immunization coverage in children <1 year of age is crucial to halting virus transmission. In 2015, a community-based vaccination (CBV) strategy, using local community members to enhance vaccine acceptance and improve routine immunization service delivery, was introduced in areas of Pakistan that have never interrupted poliovirus transmission. In order to assess progress towards improving routine immunization, we performed house-to-house immunization surveys across ten CBV areas in 2017 and 2018. In each household, we determined age-appropriate routine antigen coverage for children <1 year of age based on vaccination card and caregiver recall. We surveyed 5,499 and 5,264 children in 2017 and 2018, respectively. Overall, coverage of inactivated poliovirus vaccine (IPV) at 14 weeks of age was 32% in 2017 and 39% in 2018 based on vaccination card and recall. Across the surveyed areas, coverage ranged from 7% in Killa Abdullah to 61% in Peshawar in 2018. Oral poliovirus vaccination coverage decreased with successive vaccination visits, ranging from 66% for the birth dose to 42% for the 14-week dose in 2018. No area reached the target of 80% coverage for any routine antigen. Our findings highlight the need for concerted efforts to improve routine immunization coverage in these critical areas of wild poliovirus transmission.

•COVID-19 during pregnancy imposes a risk of severe disease and adverse birth outcomes.•Data about the safety of vaccination against COVID-19 for pregnant women is limited.•COVID-19 vaccination coverage among pregnant persons is suboptimal.•We found no safety concerns for COVID-19 vaccination during pregnancy.•Our findings support authorized or approved COVID-19 vaccines for pregnant persons. Assessment of COVID-19 vaccines safety during pregnancy is urgently needed. We conducted a systematic review and meta-analysis to evaluate the safety of COVID-19 vaccines, including their components and technological platforms used in other vaccines during pregnancy and animal studies to complement direct evidence. We searched literature databases from its inception to September 2021 without language restriction, COVID-19 vaccine websites, and reference lists of other systematic reviews and the included studies. Pairs of reviewers independently selected, data extracted, and assessed the risk of bias of the studies. Discrepancies were resolved by consensus. (PROSPERO CRD42021234185). We retrieved 8,837 records from the literature search; 71 studies were included, involving 17,719,495 pregnant persons and 389 pregnant animals. Most studies (94%) were conducted in high-income countries, were cohort studies (51%), and 15% were classified as high risk of bias. We identified nine COVID-19 vaccine studies, seven involving 309,164 pregnant persons, mostly exposed to mRNA vaccines. Among non-COVID-19 vaccines, the most frequent exposures were AS03 and aluminum-based adjuvants. A meta-analysis of studies that adjusted for potential confounders showed no association with adverse outcomes, regardless of the vaccine or the trimester of vaccination. Neither the reported rates of adverse pregnancy outcomes nor reactogenicity exceeded expected background rates, which was the case for ASO3- or aluminum-adjuvanted non-COVID-19 vaccines in the proportion meta-analyses of uncontrolled studies/arms. The only exception was postpartum hemorrhage after COVID-19 vaccination (10.40%; 95% CI: 6.49–15.10%), reported by two studies; however, the comparison with non-exposed pregnant persons, available for one study, found non-statistically significant differences (adjusted OR 1.09; 95% CI 0.56–2.12). Animal studies showed consistent results with studies in pregnant persons. We found no safety concerns for currently administered COVID-19 vaccines during pregnancy. Additional experimental and real-world evidence could enhance vaccination coverage. Robust safety data for non-mRNA-based COVID-19 vaccines are still needed.

•Pregnant persons with COVID-19 may present with severe illness and adverse pregnancy or birth outcomes.•Data about the safety of vaccination against COVID-19 for pregnant persons is limited.•COVID-19 vaccines selected by COVAX showed no evidence of pregnancy-associated safety concerns.•Pregnant persons may consider receiving these vaccines.•Benefits could be higher for pregnant persons at high risk of exposure or with comorbidities. Rapid assessment of COVID-19 vaccine safety during pregnancy is urgently needed. We conducted a rapid systematic review, to evaluate the safety of COVID-19 vaccines selected by the COVID-19 Vaccines Global Access-Maternal Immunization Working Group in August 2020, including their components and their technological platforms used in other vaccines for pregnant persons. We searched literature databases, COVID-19 vaccine pregnancy registries, and explored reference lists from the inception date to February 2021 without language restriction. Pairs of reviewers independently selected studies through COVIDENCE, and performed the data extraction and the risk of bias assessment. Discrepancies were resolved by consensus. Registered on PROSPERO (CRD42021234185). We retrieved 6757 records and 12 COVID-19 pregnancy registries from the search strategy; 38 clinical and non-clinical studies (involving 2,398,855 pregnant persons and 56 pregnant animals) were included. Most studies (89%) were conducted in high-income countries and were cohort studies (57%). Most studies (76%) compared vaccine exposures with no exposure during the three trimesters of pregnancy. The most frequent exposure was to AS03 adjuvant, in the context of A/H1N1 pandemic influenza vaccines, (n = 24) and aluminum-based adjuvants (n = 11). Only one study reported exposure to messenger RNA in lipid nanoparticles COVID-19 vaccines. Except for one preliminary report about A/H1N1 influenza vaccination (adjuvant AS03), corrected by the authors in a more thorough analysis, all studies concluded that there were no safety concerns. This rapid review found no evidence of pregnancy-associated safety concerns of COVID-19 vaccines or of their components or platforms when used in other vaccines. However, the need for further data on several vaccine platforms and components is warranted, given their novelty. Our findings support current WHO guidelines recommending that pregnant persons may consider receiving COVID-19 vaccines, particularly if they are at high risk of exposure or have comorbidities that enhance the risk of severe disease.

•Oral rotavirus vaccines are less immunogenic and effective in low-income settings.•Infant gut microbiota and micronutrient status may contribute to this phenomenon.•We did a randomised controlled trial of probiotic and zinc supplementation in India.•Probiotic was associated with a modest (7.5%) improvement in vaccine immunogenicity.•Zinc supplementation (5mg/day) did not alter zinc status or vaccine immunogenicity. Strategies are needed to improve oral rotavirus vaccine (RV), which provides suboptimal protection in developing countries. Probiotics and zinc supplementation could improve RV immunogenicity by altering the intestinal microbiota and immune function. Infants 5weeks old living in urban Vellore, India were enrolled in a randomized, double-blind, placebo-controlled trial with a 4-arm factorial design to assess the effects of daily zinc (5mg), probiotic (1010Lactobacillus rhamnosus GG) or placebo on the immunogenicity of two doses of RV (Rotarix®, GlaxoSmithKline Biologicals) given at 6 and 10weeks of age. Infants were eligible for participation if healthy, available for the study duration and without prior receipt of RV or oral poliovirus vaccine other than the birth dose. The primary outcome was seroconversion to rotavirus at 14weeks of age based on detection of VP6-specific IgA at ≥20U/ml in previously seronegative infants or a fourfold rise in concentration. The study took place during July 2012 to February 2013. 620 infants were randomized equally between study arms and 551 (88.9%) completed per protocol. Seroconversion was recorded in 54/137 (39.4%), 42/136 (30.9%), 40/143 (28.0%), and 37/135 (27.4%) infants receiving (1) probiotic and zinc, (2) probiotic and placebo, (3) placebo and zinc, (4) two placebos. Seroconversion showed a modest improvement among infants receiving probiotic (difference between groups 1, 2 and 3, 4 was 7.5% (97.5% Confidence Interval (CI): −1.4%, 16.2%), p=0.066) but not zinc (difference between groups 1, 3 and 2, 4 was 4.4% (97.5% CI: −4.4%, 13.2%), p=0.272). 16 serious adverse events were recorded, none related to study interventions. Zinc or probiotic supplementation did not significantly improve the low immunogenicity of rotavirus vaccine given to infants in a poor urban community in India. A modest effect of combined supplementation deserves further investigation. The trial was registered in India (CTRI/2012/05/002677).

SARS-CoV-2 vaccines are highly effective in preventing severe COVID-19 but require boosting to maintain protection. Changes to circulating variants and prevalent natural immunity may impact on real-world effectiveness of boosters. With NHS England approval, we used linked routine clinical data from >24 million patients to evaluate the effectiveness of the 2022 combined COVID-19 autumn booster and influenza vaccine campaign in non-clinically vulnerable 50-year-olds in England using a regression discontinuity design. Our primary outcome was a composite of 6-week COVID-19 emergency attendance, COVID-19 unplanned hospitalisation, or death. By 26 November 2022, booster vaccine coverage was 11.1 % at age 49.75 years increasing to 39.7 % at age 50.25 years. The estimated effect of the campaign on the risk of the primary outcome in 50-year-olds during weeks 7–12 after the start of the campaign was −0.4 per 100,000 (95 % CI -7.8, 7.1). The results were similar when using different follow-up start dates or when estimating the effect of vaccination (rather than the campaign). This study found little evidence that the autumn 2022 vaccination campaign in England was associated with a reduction in severe COVID-19-related outcomes among non-clinically vulnerable 50-year-olds. Possible explanations include the low risk of severe outcomes and substantial pre-existing vaccine- and infection-induced immunity. The booster campaign may have had effects beyond those we estimated, including reducing virus transmission and incidence of mild or moderate COVID-19. •Among non-clinically vulnerable 50-year-olds eligible for booster vaccination, this study did not observe any reduction in severe COVID-19 outcomes associated with the 2022 autumn booster campaign.•Booster coverage was modest among non-clinically vulnerable people ≥50 years.•The risk of severe COVID-19 outcomes was low in this population, in part due to high pre-existing vaccine- and infection-induced immunity.

Stopping serotype 1 wild poliovirus transmission in Pakistan and Afghanistan requires ensuring all children <5 years of age are repeatedly vaccinated, including the large proportion living in mobile groups. Vaccinating children living in high-risk mobile populations (HRMPs) remains a priority for the polio programme. In 2017–2018, group-level censuses were conducted in 43 districts of Pakistan, gathering information for all HRMP children <5 years of age residing in settlements. Demographic and mobility information was collected, including HRMP type, ethnicity, language, mode of transportation and movement patterns. Vaccination status was recorded for the most recent polio campaign. Proportion of HRMP children by demographic factors and mode of transportation was determined and the magnitude of movement was quantified based on the origin, previous and next locations. Magnitude of cross-border movement with Afghanistan was evaluated, as was primary crossing point. Vaccination status was evaluated for each district by demographic and mode of transportation information. In total, 188,130 HRMP children <5 years of age were assessed. The predominant HRMP type, ethnic group, language and mode of transport was Afghan refugees (27%), Pashtun (69%), Pashto (69%) and bus (52%). Overall, 84% of children originated outside of their current district, including 29% from Afghanistan. Previous and next locations, were reported outside of current location by 34% and 77% of children. Afghanistan was previous and next location for 5% and 11% of children, with 5.5% and 3% of children crossing the Afghanistan border in the past 6-months and next 3-months. Primary crossing route was Torkham (79%). Overall vaccination coverage was 98% (IQR: 96%-99%) and consistently >90% across HRMP type, ethnic group, language and mobility means. Large numbers of HRMPs were found across Pakistan, with substantial links throughout the country and with Afghanistan. While vaccination coverage of HRMPs was high, ensuring these populations are consistently vaccinated remains a priority.

Abstract Background Health-seeking behavior and health care access (HSB/HCA) are recognized confounders in many observational studies but are not directly measurable in electronic health records. We used proxy markers of HSB/HCA to quantify and adjust for confounding in observational studies of influenza and COVID-19 vaccine effectiveness (VE). Methods This cohort study used primary care data prelinked to secondary care and death data in England. We included individuals aged ≥66 years on 1 September 2019 and assessed influenza VE in the 2019–2020 season and early COVID-19 VE (December 2020–March 2021). VE was estimated with sequential adjustment for demographics, comorbidities, and 14 markers of HSB/HCA. Influenza vaccination in the 2019–2020 season was also considered a negative control exposure against COVID-19 before COVID-19 vaccine rollout. Results We included 1 991 284, 1 796 667, and 1 946 943 individuals in the influenza, COVID-19, and negative control exposure populations, respectively. Markers of HSB/HCA were positively correlated with influenza and COVID-19 vaccine uptake. For influenza, adjusting for HSB/HCA markers in addition to demographics and comorbidities increased VE against influenza-like illness from −1.5% (95% CI, −3.2% to .1%) to 7.1% (95% CI, 5.4%–8.7%) with a less apparent trend for more severe outcomes. For COVID-19, adjusting for HSB/HCA markers did not change VE estimates against infection or severe disease (eg, 2 doses of BNT162b2 against infection: 82.8% [95% CI, 78.4%–86.3%] to 83.1% [95% CI, 78.7%–86.5%]). Adjusting for HSB/HCA markers removed bias in the negative control exposure analysis (−7.5% [95% CI, −10.6% to −4.5%] vs −2.1% [95% CI, −6.0% to 1.7%] before vs after adjusting for HSB/HCA markers). Conclusions Markers of HSB/HCA can be used to quantify and account for confounding in observational vaccine studies.

This Web Watch introduces the VaC tracker, a web resource that features an overview of the COVID-19 ‘vaccine landscape’, a clinical trials database and a ‘living review’ that distils the results of vaccine trials as they become available.