Infant Non-Secretor Histoblood Group Antigen Phenotype Reduces Susceptibility to Both Symptomatic and Asymptomatic Rotavirus Infection.

The infant non-secretor histoblood group antigen phenotype is associated with reduced risk of symptomatic rotavirus diarrhea, one of the leading global causes of severe pediatric diarrheal disease and mortality. However, little is known regarding the role of secretor status in asymptomatic rotavirus infections. Therefore, we performed a nested case-control study within a birth cohort study previously conducted in Dhaka, Bangladesh, to determine the association between infant secretor phenotype and the odds of asymptomatic rotavirus infection, in addition to the risk of rotavirus diarrhea, in unvaccinated infants. In the parent cohort, infants were enrolled in the first week of life and followed through the first two years of life with multiple clinic visits and active surveillance for diarrheal illness. Secretor phenotyping was performed on saliva. Eleven surveillance stools collected over the first year of life were tested for rotavirus by real-time RT-PCR, followed by conventional PCR and amplicon sequencing to identify the infecting P-type of positive specimens. Similar to findings for symptomatic diarrhea, infant non-secretors experienced significantly fewer primary episodes of asymptomatic rotavirus infection through the first year of life in a likely rotavirus P-genotype-dependent manner. These data suggest that non-secretors experienced reduced risk from rotavirus due to decreased susceptibility to infection rather than reduced infection severity.

Genetic Susceptibility to Astrovirus Diarrhea in Bangladeshi Infants.

Background: Astroviral infections commonly cause acute nonbacterial gastroenteritis in children globally. However, these infections often go undiagnosed outside of research settings. There is no treatment available for astrovirus, and Astroviridae strain diversity presents a challenge to potential vaccine development. Methods: To address our hypothesis that host genetic risk factors are associated with astrovirus disease susceptibility, we performed a genome-wide association study of astrovirus infection in the first year of life from children enrolled in 2 Bangladeshi birth cohorts. Results: We identified a novel region on chromosome 1 near the loricrin gene (LOR) associated with astrovirus diarrheal infection (rs75437404; meta-analysis P = 8.82 × 10-9; A allele odds ratio, 2.71) and on chromosome 10 near the prolactin releasing hormone receptor gene (PRLHR) (rs75935441; meta-analysis P = 1.33 × 10-8; C allele odds ratio, 4.17). The prolactin-releasing peptide has been shown to influence feeding patterns and energy balance in mice. In addition, several single-nucleotide polymorphisms in the chromosome 1 locus have previously been associated with expression of innate immune system genes PGLYRP4, S100A9, and S100A12. Conclusions: This study identified 2 significant host genetic regions that may influence astrovirus diarrhea susceptibility and should be considered in further studies.

TV005 dengue vaccine protects against dengue serotypes 2 and 3 in two controlled human infection studies.

BACKGROUNDDisease due to dengue viruses is a growing global health threat, causing 100-400 million cases annually. An ideal dengue vaccine should demonstrate durable protection against all 4 serotypes in phase III efficacy trials, however the lack of circulating serotypes may lead to incomplete efficacy data. Controlled human infection models help downselect vaccine candidates and supply critical data to supplement efficacy trials. We evaluated the efficacy of a leading live-attenuated tetravalent dengue vaccine candidate, TV005, against infection with a newly established dengue serotype 3 or an established serotype 2 challenge virus.METHODSTwo randomized, controlled clinical trials were performed. In study 1, a total of 42 participants received TV005 or placebo (n = 21 each), and 6 months later, all were challenged with dengue 2 virus (rDEN2Δ30) at a dose of 103 PFU. In study 2, a total of 23 participants received TV005 and 20 received placebo, and 6 months later, all were challenged with 104 PFU dengue 3 virus (rDEN3Δ30). The study participants were closely monitored for safety, viremia, and immunologic responses. Infection, measured by post-challenge viremia, and the occurrence of rash and neutropenia were the primary endpoints. Secondary endpoints included safety, immunologic, and virologic profiles following vaccination with TV005 and subsequent challenge with the rDEN2Δ30 or rDEN3Δ30 strain.RESULTSTV005 was well tolerated and protected all vaccinated volunteers from viremia with DENV2 or DENV3 (none infected in either group). Placebo recipients had post-challenge viremia (100% in study 1, 85% in study 2), and all experienced rash following challenge with either serotype.CONCLUSIONSTV005 is a leading tetravalent dengue vaccine candidate that fully protected against infection with DENV2 and DENV3 in an established controlled human infection model.TRIAL REGISTRATIONClinicalTrials.gov NCT02317900 and NCT02873260.FUNDINGIntramural Research Program, NIH (contract HHSN272200900010C).

Safety and durable immunogenicity of the TV005 tetravalent dengue vaccine, across serotypes and age groups, in dengue-endemic Bangladesh: a randomised, controlled trial.

BACKGROUND: Morbidity and mortality from dengue virus (DENV) is rapidly growing in the large populations of south Asia. Few formal evaluations of candidate dengue vaccine candidates have been undertaken in India, Pakistan, or Bangladesh. Tetravalent vaccines must be tested for safety and immunogenicity in all age groups and in those previously exposed and naive to DENV infections. TV005 is a live, attenuated tetravalent dengue vaccine. We evaluated the safety and immunogenicity of a single dose of TV005 across age groups in dengue-endemic Bangladesh. METHODS: We performed a randomised, placebo-controlled age de-escalating clinical trial of TV005 at a single clinical site in dengue-endemic Dhaka, Bangladesh, following a technology transfer from the USA. Healthy (as determined by history, clinical examination, and safety laboratory test results) volunteers aged 1-50 years were randomly assigned 3:1 (stratified by four age groups) to receive a single dose of TV005 vaccine or placebo. Participants were followed up for 3 years. The study was double blind and was unmasked at day 180; outcome assessors, clinic staff, and volunteers remained blind throughout. Primary outcomes were safety, evaluated per-protocol as proportion of volunteers with solicited related adverse events of any severity through 28 days post dosing, and post-vaccination seropositivity by day 180 using serotype-specific neutralising antibodies (PRNT50 ≥10). Secondary outcomes included viremia, impact of past dengue exposure, and durability of antibody responses. This study is registered with Clinicaltrials.gov, NCT02678455, and is complete. FINDINGS: Between March 13, 2016, and Feb 14, 2017, 192 volunteers were enrolled into four age groups (adults [18-50 years; 20 male and 28 female], adolescents [11-17 years; 27 male and 21 female], children [5-10 years; 15 male and 33 female], and young children [1-4 years; 29 male and 19 female]) with 48 participant per group. All participants were Bangladeshi. Vaccination was well tolerated and most adverse events were mild. Rash was the most common vaccine-associated solicited adverse event, in 37 (26%) of 144 vaccine recipients versus six (12%) of 48 placebo recipients; followed by fever in seven (5% of 144) and arthralgias in seven (6% of 108), which were only observed in vaccine recipients. Post-vaccine, volunteers of all ages (n=142) were seropositive to most serotypes with 118 (83%) seropositive to DENV 1, 141 (99%) to DENV 2, 137 (96%) to DENV 3, and 124 (87%) to DENV 4, overall by day 180. Post-vaccination, viraemia was not consistently found and antibody titres were higher (10-15-fold for DENV 1-3 and 1·6-fold for DENV 4) in individuals with past dengue exposure compared with the dengue-naive participants (DENV 1 mean 480 [SD 4·0] vs 32 [2·4], DENV 2 1042 [3·2] vs 105 [3·1], DENV 3 1406 [2·8] vs 129 [4·7], and DENV 4 105 [3·3] vs 65 [3·1], respectively). Antibody titres to all serotypes remained stable in most adults (63-86%) after 3 years of follow-up. However, as expected for individuals without past exposure to dengue, titres for DENV 1, 3, and 4 waned by 3 years in the youngest (1-4 year old) cohort (69% seropositive for DENV 2 and 22-28% seropositive for DENV 1, 3, and 4). INTERPRETATION: With 3 years of follow-up, the single-dose tetravalent dengue vaccine, TV005, was well tolerated and immunogenic for all four serotypes in young children to adults, including individuals with no previous dengue exposure. FUNDING: National Institutes of Health-National Institute of Allergy and Infectious Diseases Intramural Research Program and Johns Hopkins University. TRANSLATION: For the Bangla translation of the abstract see Supplementary Materials section.

Network analysis of patterns and relevance of enteric pathogen co-infections among infants in a diarrhea-endemic setting.

Despite significant progress in recent decades toward ameliorating the excess burden of diarrheal disease globally, childhood diarrhea remains a leading cause of morbidity and mortality in low-and-middle-income countries (LMICs). Recent large-scale studies of diarrhea etiology in these populations have revealed widespread co-infection with multiple enteric pathogens, in both acute and asymptomatic stool specimens. We applied methods from network science and ecology to better understand the underlying structure of enteric co-infection among infants in two large longitudinal birth cohorts in Bangladesh. We used a configuration model to establish distributions of expected random co-occurrence, based on individual pathogen prevalence alone, for every pathogen pair among 30 enteropathogens detected by qRT-PCR in both diarrheal and asymptomatic stool specimens. We found two pairs, Enterotoxigenic E. coli (ETEC) with Enteropathogenic E. coli (EPEC), and ETEC with Campylobacter spp., co-infected significantly more than expected at random (both pairs co-occurring almost 4 standard deviations above what one could expect due to chance alone). Furthermore, we found a general pattern that bacteria-bacteria pairs appear together more frequently than expected at random, while virus-bacteria pairs tend to appear less frequently than expected based on model predictions. Finally, infants co-infected with leading bacteria-bacteria pairs had more days of diarrhea in the first year of life compared to infants without co-infection (p-value <0.0001). Our methods and results help us understand the structure of enteric co-infection which can guide further work to identify and eliminate common sources of infection or determine biologic mechanisms that promote co-infection.

Differences in Rotavirus Shedding and Duration by Infant Oral Rotavirus Vaccination Status in Dhaka, Bangladesh 2011 - 2014.

To evaluate how breakthrough rotavirus disease contributes to transmission, we examined the impact of rotavirus vaccination on fecal shedding and duration of illness. We used multivariable linear regression to analyze rotavirus quantity by RT-qPCR and duration among 184 episodes of rotavirus diarrhea positive by ELISA in the PROVIDE study. Vaccinated children had less fecal viral shedding compared to unvaccinated children (mean difference = -0.59 log copies per gram of stool, 95% CI: -0.99, -0.19). Duration of illness was on average 0.47 days (95% CI: -0.23, 1.17) shorter among vaccinated children. Rotarix vaccination reduces shedding burden among breakthrough cases of RVGE.

We estimated the effect of rotavirus vaccination on duration and quantity of rotavirus shed during rotavirus gastroenteritis in Bangladesh. Virus quantity was lower in symptomatic vaccinated children compared to symptomatic unvaccinated children, but differences in episode duration were small.

Targeting hepatitis B vaccine escape using immunogenetics in Bangladeshi infants.

Hepatitis B virus (HBV) vaccine escape mutants (VEM) are increasingly described, threatening progress in control of this virus worldwide. Here we studied the relationship between host genetic variation, vaccine immunogenicity and viral sequences implicating VEM emergence. In a cohort of 1,096 Bangladeshi children, we identified human leukocyte antigen (HLA) variants associated with response vaccine antigens. Using an HLA imputation panel with 9,448 south Asian individuals DPB1*04:01 was associated with higher HBV antibody responses (p=4.5×10-30). The underlying mechanism is a result of higher affinity binding of HBV surface antigen epitopes to DPB1*04:01 dimers. This is likely a result of evolutionary pressure at the HBV surface antigen 'a-determinant' segment incurring VEM specific to HBV. Prioritizing pre-S isoform HBV vaccines may tackle the rise of HBV vaccine evasion.

Maternal Breast Milk Secretor Phenotype Does Not Affect Infant Susceptibility to Rotavirus Diarrhea.

Breast milk secretor status is associated with antibody seroconversion to oral rotavirus vaccination. Here, we were unable to detect a similar impact on risk of infant rotavirus diarrhea or vaccine efficacy through 2 years of life, underscoring limitations of immunogenicity assessment alone in evaluation of oral rotavirus vaccine response.

Genome-Wide Association Studies of Diarrhea Frequency and Duration in the First Year of Life in Bangladeshi Infants.

BACKGROUND: Diarrhea is the second leading cause of death in children under 5 years old worldwide. Known diarrhea risk factors include sanitation, water sources, and pathogens but do not fully explain the heterogeneity in frequency and duration of diarrhea in young children. We evaluated the role of host genetics in diarrhea. METHODS: Using 3 well-characterized birth cohorts from an impoverished area of Dhaka, Bangladesh, we compared infants with no diarrhea in the first year of life to those with an abundance, measured by either frequency or duration. We performed a genome-wide association analysis for each cohort under an additive model and then meta-analyzed across the studies. RESULTS: For diarrhea frequency, we identified 2 genome-wide significant loci associated with not having any diarrhea, on chromosome 21 within the noncoding RNA AP000959 (C allele odds ratio [OR] = 0.31, P = 4.01 × 10-8), and on chromosome 8 within SAMD12 (T allele OR = 0.35, P = 4.74 × 10-7). For duration of diarrhea, we identified 2 loci associated with no diarrhea, including the same locus on chromosome 21 (C allele OR = 0.31, P = 1.59 × 10-8) and another locus on chromosome 17 near WSCD1 (C allele OR = 0.35, P = 1.09 × 10-7). CONCLUSIONS: These loci are in or near genes involved in enteric nervous system development and intestinal inflammation and may be potential targets for diarrhea therapeutics.

Association of Symptoms After COVID-19 Vaccination With Anti-SARS-CoV-2 Antibody Response in the Framingham Heart Study.

This cohort study examines the association of self-reported postvaccination symptoms with anti­SARS-CoV-2 antibody response among Framingham Heart Study participants contributing to the Collaborative Cohort of Cohorts for COVID-19 Research study.

Intradermal fractional-dose inactivated polio vaccine (fIPV) adjuvanted with double mutant Enterotoxigenic Escherichia coli heat labile toxin (dmLT) is well-tolerated and augments a systemic immune response to all three poliovirus serotypes in a randomized placebo-controlled trial.

Eradication of poliomyelitis globally is constrained by fecal shedding of live polioviruses, both wild-type and vaccine-derived strains, into the environment. Although inactivated polio vaccines (IPV) effectively protect the recipient from clinical poliomyelitis, fecal shedding of live virus still occurs following infection with either wildtype or vaccine-derived strains of poliovirus. In the drive to eliminate the last cases of polio globally, improvements in both oral polio vaccines (OPV) (to prevent reversion to virulence) and injectable polio vaccines (to improve mucosal immunity and prevent viral shedding) are underway. The E. coli labile toxin with two or "double" attenuating mutations (dmLT) may boost immunologic responses to IPV, including at mucosal sites. We performed a double-blinded phase I controlled clinical trial to evaluate safety, tolerability, as well as systemic and mucosal immunogenicity of IPV adjuvanted with dmLT, given as a fractional (1/5th) dose intradermally (fIPV-dmLT). Twenty-nine volunteers with no past exposure to OPV were randomized to a single dose of fIPV-dmLT or fIPV alone. fIPV-dmLT was well tolerated, although three subjects had mild but persistent induration and hyperpigmentation at the injection site. A ≥ 4-fold rise in serotype-specific neutralizing antibody (SNA) titers to all three serotypes was seen in 84% of subjects receiving fIPV-dmLT vs. 50% of volunteers receiving IPV alone. SNA titers were higher in the dmLT-adjuvanted group, but only differences in serotype 1 were significant. Mucosal immune responses, as measured by polio serotype specific fecal IgA were minimal in both groups and differences were not seen. fIPV-dmLT may offer a benefit over IPV alone. Beyond NAB responses protecting the individual, studies demonstrating the ability of fIPV-dmLT to prevent viral shedding are necessary. Studies employing controlled human infection models, using monovalent OPV post-vaccine are ongoing. Studies specifically in children may also be necessary and additional biomarkers of mucosal immune responses in this population are needed. Clinicaltrials.gov Identifer: NCT03922061.

Genome-Wide Association Study of Campylobacter-Positive Diarrhea Identifies Genes Involved in Toxin Processing and Inflammatory Response.

Diarrhea is responsible for the deaths of more than 500,000 children each year, many of whom reside in low-to-middle-income countries (LMICs). Additionally, children with multiple diarrheal infections early in life have increased growth stunting and malnutrition and decreased vaccine efficacy. Two bacteria that contribute to the burden of diarrhea are Campylobacter jejuni and Campylobacter coli, both are endemic in Bangladesh. However, not all children that are exposed to these pathogens, including Campylobacter, will experience diarrhea. We hypothesized that host genetics may influence susceptibility to Campylobacter infections and performed a genome-wide association study in 534 children from two independent birth cohorts in Dhaka, Bangladesh. Infants were monitored for diarrhea for the first 2 years of life and only defined as controls if all diarrheal samples in the first year were negative for Campylobacter jejuni/C. coli. Each cohort was analyzed separately under an additive model and adjusted for length-for-age z-scores at birth and 12 months, sex, water treatment, and ancestry. In a fixed effect inverse-variance weighted meta-analysis of these two cohorts, we identified a genome-wide significant region on chromosome 8 in intron 4 of the rho guanine nucleotide exchange factor 10 gene (ARHGEF10). Individuals with the G allele (rs13281104) had a 2-fold lower risk of having a Campylobacter-associated diarrheal episode than individuals with the A allele (OR 0.41, 95% CI 0.29 to 0.58, P = 3.6 × 10-7). This SNP is associated with decreased expression of the neighboring gene, CLN8, which may be involved in the transport of the cytolethal distending toxin produced by Campylobacter. IMPORTANCE Children in low-to-middle-income countries often suffer from multiple enteric infections in their first few years of life, many of which have the potential for long-lasting effects. These children are already likely to be malnourished and underweight, and chronic intestinal disturbances exacerbate these conditions. Despite public health interventions aimed at improving water, sanitation, and hygiene, enteric infections are still a leading cause of death for children under five. Previous work has included transmission dynamics, pathogen characteristics, and evaluation of interventions. Here, we examined the role of host genetic variation in susceptibility to diarrhea-associated Campylobacter infection. In our meta-analysis of two independent birth cohorts from Dhaka, Bangladesh, we found that children carrying a specific genetic variant (rs13281104, in an intron of ARHGEF10) were half as likely to have a diarrhea-associated Campylobacter infection in their first year of life. This protective effect may be achieved by decreasing gene expression and thereby impacting host-pathogen interactions and host immune response.

Plasma VP8∗-Binding Antibodies in Rotavirus Infection and Oral Vaccination in Young Bangladeshi Children.

BACKGROUND: Despite the availability and success of live-attenuated oral vaccines, rotavirus (RV) remains the leading cause of pediatric gastroenteritis worldwide. Next-generation vaccines targeting RV VP8∗ are under evaluation, but the role of VP8∗-specific antibodies in human immunity to RV and their potential as immune correlates of protection remains underexplored. METHODS: We measured plasma RV VP8∗-binding antibodies in 2 cohorts of young children in Dhaka, Bangladesh. Plasma from a cohort study of 137 unvaccinated children aged 6-24 months old hospitalized with acute gastroenteritis was assessed for VP8∗ antibody seropositivity. VP8∗ antibodies were compared with the current standard for RV immunity, total RV-specific IgA (RV-IgA). Additionally, VP8∗ antibody responses were measured as part of an immunogenicity trial of a monovalent, oral, live-attenuated RV vaccine (Rotarix). RESULTS: Fewer children with acute RV gastroenteritis were seropositive for VP8∗-binding IgA or IgG antibodies at hospital admission compared with RV-IgA, suggesting that the absence of VP8∗-binding antibodies more accurately predicts susceptibility to RV gastroenteritis than RV-IgA in unvaccinated children. However, when present, these antibodies appeared insufficient to protect fully from disease and no threshold antibody level for protection was apparent. In vaccinated children, these antibodies were very poorly induced by Rotarix vaccine, suggesting that VP8∗-specific antibodies alone are not necessary for clinical protection following oral vaccination. CONCLUSIONS: This work suggests that VP8∗-binding antibodies may not be sufficient or necessary for protection from RV gastroenteritis following prior RV infection or oral vaccination; the role of VP8∗ antibodies induced by parenteral vaccination with non-replicating vaccines remains to be determined.

A site assessment tool for inpatient controlled human infection models for enteric disease pathogens.

The use of the controlled human infection model to facilitate product development and to advance understanding of host-pathogen interactions is of increasing interest. While administering a virulent (or infective) organism to a susceptible host necessitates an ongoing evaluation of safety and ethical considerations, a central theme in conducting these studies in a safe and ethical manner that yields actionable data is their conduct in facilities well-suited to address their unique attributes. To that end, we have developed a framework for evaluating potential sites in which to conduct inpatient enteric controlled human infection model to ensure consistency and increase the likelihood of success.

Oral rotavirus vaccine shedding as a marker of mucosal immunity.

Group A rotaviruses (RVA) remain a leading cause of pediatric diarrhea worldwide, in part due to underperformance of currently approved live-attenuated, oral vaccines in low-and-middle income countries. Improved immune correlates of protection (CoP) for existing oral vaccines and novel strategies to evaluate the performance of next-generation vaccines are needed. Use of oral vaccines as challenge agents in controlled human infection models is a potential approach to CoP discovery that remains underexplored. In a live-attenuated, oral rotavirus vaccine (Rotarix, GlaxoSmithKline) efficacy trial conducted among infants in Dhaka, Bangladesh, we explored the potential for the second dose of the two-dose series to be considered a challenge agent through which RVA immunity could be explored, using fecal virus shedding post-dose 2 as a marker of mucosal immunity. Among 180 vaccinated infants who completed the parent study per protocol, the absence of fecal vaccine shedding following the second dose of Rotarix suggested intestinal mucosal immunity generated by the first dose and a decreased risk of RVA diarrhea through 2 years of life (RR 0.616, 95% CI 0.392-0.968). Further development of controlled human infection models for group A rotaviruses, especially in prospective studies with larger sample sizes, may be a promising tool to assess rotavirus vaccine efficacy and CoPs.

SARS CoV-2 seroprevalence in a US school district during COVID-19.

Reduced symptomatology and access to testing in children have led to underestimates of paediatric COVID-19 prevalence and raised concerns about school safety. To explore COVID-19 prevalence and risk factors in school settings, we conducted a SARS-CoV-2 serosurvey in a Vermont, USA school district in December 2020. Among 336 students (63%) and 196 teachers/staff (37%), adjusted seroprevalence was 4.7% (95% CI 2.9 to 7.2) and was lowest in preK-5 students (4-10 Years). Seroprevalence was 10-fold higher than corresponding state PCR data but was low overall with no evidence of onward transmissions. These results further support feasibility of in-person learning during COVID-19 with appropriate mitigation measures.

Associations between biomarkers of environmental enteric dysfunction and oral rotavirus vaccine immunogenicity in rural Zimbabwean infants.

BACKGROUND: Oral rotavirus vaccines (RVV) are poorly immunogenic in low-income countries. Environmental enteric dysfunction (EED) resulting from poor water, sanitation and hygiene (WASH) may contribute. We therefore tested associations between EED and RVV immunogenicity, and evaluated the effect of improved WASH on EED. METHODS: We measured nine biomarkers of EED among Zimbabwean infants born to mothers enrolled in a cluster-randomised 2 × 2 factorial trial of improved WASH and improved feeding between November 2012 and March 2015 (NCT01824940). We used multivariable regression to determine associations between EED biomarkers and RVV seroconversion, seropositivity and geometric mean titer. Log-binomial regression was used to evaluate the effect of improved WASH on EED. FINDINGS: Among 303 infants with EED biomarkers and immunogenicity data, plasma intestinal fatty-acid binding protein and stool myeloperoxidase were positively associated with RVV seroconversion; adjusted RR 1.63 (95%CI 1.04, 2.57) and 1.29 (95%CI 1.01, 1.65), respectively. There were no other associations between RVV immunogenicity and either individual biomarkers or EED domains (intestinal permeability, intestinal damage, intestinal inflammation and microbial translocation). EED biomarkers did not differ between randomised WASH and non-WASH groups. INTERPRETATION: We found no evidence that EED was associated with poor RVV immunogenicity. Contrary to our hypothesis, there was weak evidence that EED was associated with increased seroconversion. EED biomarkers were not affected by a package of household-level WASH interventions.

Phase 3 Safety and Efficacy of AZD1222 (ChAdOx1 nCoV-19) Covid-19 Vaccine.

BACKGROUND: The safety and efficacy of the AZD1222 (ChAdOx1 nCoV-19) vaccine in a large, diverse population at increased risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the United States, Chile, and Peru has not been known. METHODS: In this ongoing, double-blind, randomized, placebo-controlled, phase 3 clinical trial, we investigated the safety, vaccine efficacy, and immunogenicity of two doses of AZD1222 as compared with placebo in preventing the onset of symptomatic and severe coronavirus disease 2019 (Covid-19) 15 days or more after the second dose in adults, including older adults, in the United States, Chile, and Peru. RESULTS: A total of 32,451 participants underwent randomization, in a 2:1 ratio, to receive AZD1222 (21,635 participants) or placebo (10,816 participants). AZD1222 was safe, with low incidences of serious and medically attended adverse events and adverse events of special interest; the incidences were similar to those observed in the placebo group. Solicited local and systemic reactions were generally mild or moderate in both groups. Overall estimated vaccine efficacy was 74.0% (95% confidence interval [CI], 65.3 to 80.5; P<0.001) and estimated vaccine efficacy was 83.5% (95% CI, 54.2 to 94.1) in participants 65 years of age or older. High vaccine efficacy was consistent across a range of demographic subgroups. In the fully vaccinated analysis subgroup, no severe or critical symptomatic Covid-19 cases were observed among the 17,662 participants in the AZD1222 group; 8 cases were noted among the 8550 participants in the placebo group (<0.1%). The estimated vaccine efficacy for preventing SARS-CoV-2 infection (nucleocapsid antibody seroconversion) was 64.3% (95% CI, 56.1 to 71.0; P<0.001). SARS-CoV-2 spike protein binding and neutralizing antibodies increased after the first dose and increased further when measured 28 days after the second dose. CONCLUSIONS: AZD1222 was safe and efficacious in preventing symptomatic and severe Covid-19 across diverse populations that included older adults. (Funded by AstraZeneca and others; ClinicalTrials.gov number, NCT04516746.).

The fecal microbiome and rotavirus vaccine immunogenicity in rural Zimbabwean infants.

BACKGROUND: Oral rotavirus vaccine (RVV) immunogenicity is considerably lower in low- versus high-income populations; however, the mechanisms underlying this remain unclear. Previous evidence suggests that the gut microbiota may contribute to differences in oral vaccine efficacy. METHODS: We performed whole metagenome shotgun sequencing on stool samples and measured anti-rotavirus immunoglobulin A in plasma samples from a subset of infants enrolled in a cluster randomized 2 × 2 factorial trial of improved water, sanitation and hygiene and infant feeding in rural Zimbabwe (SHINE trial: NCT01824940). We examined taxonomic microbiome composition and functional metagenome features using random forest models, differential abundance testing and regression analyses to explored associations with RVV immunogenicity. RESULTS: Among 158 infants with stool samples and anti-rotavirus IgA titres, 34 were RVV seroconverters. The median age at stool collection was 43 days (IQR: 35-68), corresponding to a median of 4 days before the first RVV dose. The infant microbiome was dominated by Bifidobacterium longum. The gut microbiome differed significantly between early (≤42 days) and later samples (>42 days) however, we observed no meaningful differences in alpha diversity, beta diversity, species composition or functional metagenomic features by RVV seroconversion status. Bacteroides thetaiotaomicron was the only species associated with anti-rotavirus IgA titre. Random forest models poorly classified seroconversion status by both composition and functional microbiome variables. CONCLUSIONS: RVV immunogenicity is low in this rural Zimbabwean setting, however it was not associated with the composition or function of the early-life gut microbiome in this study. Further research is warranted to examine the mechanisms of poor oral RVV efficacy in low-income countries.