Live Oral Rotavirus Vaccines Research Articles

Live Rotavirus Vaccination Appears Low-risk in Infants Born to Mothers With Inflammatory Bowel Disease on Biologics

Biologic therapies in the context of inflammatory bowel disease and pregnancy lead to improved maternal and fetal outcomes. Placental transfer results in detectable drug concentrations in infants. Rotavirus infection results in diarrheal related hospitalizations; however, the live oral vaccine is not currently recommended in biologic exposed infants. The aim of this study was to assess the effect of maternal biologic therapies on the infant immune system and safety of live rotavirus vaccination in biologic-exposed infants. Biologic-exposed infants underwent standardized clinical assessments, drug concentration, and immune function testing (complete blood count, differential, immunoglobulin levels, extended B-cell and T-cell subset enumeration, Recent Thymic Emigrants, regulatory T-cell numbers, mitogen stimulation assays, and review of T-cell Receptor Excision Circles in the newborn screen). Rotavirus vaccine-specific adverse effects following immunizations up to 42 days post the last dose of the vaccine series were recorded. There were 57 infants born to 52 mothers with inflammatory bowel disease exposed to infliximab (n= 21), adalimumab (n= 19), vedolizumab (n= 10), and ustekinumab (n= 7) in the third trimester for a median of 39 weeks (interquartile range, 38-39 weeks) at delivery. Immunologic assessments validated for age were normal in all infants despite median infliximab concentrations of 6.1 ug/mL (range, 0.4-28.8 ug/mL), adalimumab concentrations of 1.7ug/mL (range, 0.7-7.9 ug/mL), ustekinumab concentrations of 0.6 ug/mL (range, 0-1.1), and undetectable for vedolizumab at 10.7 weeks (interquartile range, 9.4-12.4) of age. The live oral rotavirus vaccine series was provided to 50 infants with the first dose given at a median of 13weeks of age. No adverse effects following immunization were reported. Immune function testing was normal, and administration of live rotavirus vaccination appeared low-risk in biologic-exposed infants irrespective of circulating drug levels.

Impact of dosing schedules on performance of rotavirus vaccines in Ghana.

Available live-oral rotavirus vaccines are associated with low to moderate performance in low- and middle-income settings. There is limited evidence relating to how the vaccine dosing schedule might be adjusted to improve vaccine performance in these settings. We used mathematical models fitted to rotavirus surveillance data for children <5 years of age from three different hospitals in Ghana (Korle-Bu Teaching Hospital in Accra, Komfo Anokye Teaching Hospital in Kumasi and War Memorial Hospital in Navrongo) to project the impact of rotavirus vaccination over a 10-year period (April 2012-March 2022). We quantified and compared the impact of the previous vaccination program in Ghana to the model-predicted impact for other vaccine dosing schedules across the three hospitals and the entire country, under different assumptions about vaccine protection. To project the rotavirus vaccine impact over Ghana, we sampled from the range of model parameters for Accra and Navrongo, assuming that these two settings represent the "extremes" of rotavirus epidemiology within Ghana. For the previously implemented 6/10-week monovalent Rotarix vaccine (RV1) schedule, the model-estimated average annual incidence of moderate-to-severe rotavirus-associated gastroenteritis (RVGE) ranged between 1,151 and 3,002 per 100,000 people per year over the 10-year period for the three sites. Compared to no vaccination, the model-estimated median percentage reductions in RVGE ranged from 28-85% and 12-71% among children <1 year and <5 years of age respectively, with the highest and lowest percentage reductions predicted using model parameters estimated for Accra and Navrongo, respectively. The median predicted reductions in RVGE for the whole country ranged from 57-66% and 35-45% among children <1 year and <5 years of age, respectively. The 1/6/10- and 6/10/14-week schedules provided the best and comparable reductions in RVGE compared to the original 6/10-week schedule, whereas there was no improvement in impact for the 10/14-week schedule. We found that administering an additional dose of RV1 might be an effective strategy to improve rotavirus vaccine impact, particularly in settings with low vaccine effectiveness. The results could be extrapolated to other countries using a 2-dose vaccine schedule with low to moderate vaccine performance.

Production of OSU G5P[7] Porcine Rotavirus Expressing a Fluorescent Reporter via Reverse Genetics.

Rotaviruses are a significant cause of severe, potentially life-threatening gastroenteritis in infants and the young of many economically important animals. Although vaccines against porcine rotavirus exist, both live oral and inactivated, their effectiveness in preventing gastroenteritis is less than ideal. Thus, there is a need for the development of new generations of porcine rotavirus vaccines. The Ohio State University (OSU) rotavirus strain represents a Rotavirus A species with a G5P[7] genotype, the genotype most frequently associated with rotavirus disease in piglets. Using complete genome sequences that were determined via Nanopore sequencing, we developed a robust reverse genetics system enabling the recovery of recombinant (r)OSU rotavirus. Although rOSU grew to high titers (~107 plaque-forming units/mL), its growth kinetics were modestly decreased in comparison to the laboratory-adapted OSU virus. The reverse genetics system was used to generate the rOSU rotavirus, which served as an expression vector for a foreign protein. Specifically, by engineering a fused NSP3-2A-UnaG open reading frame into the segment 7 RNA, we produced a genetically stable rOSU virus that expressed the fluorescent UnaG protein as a functional separate product. Together, these findings raise the possibility of producing improved live oral porcine rotavirus vaccines through reverse-genetics-based modification or combination porcine rotavirus vaccines that can express neutralizing antigens for other porcine enteric diseases.

Normal Infant Immunologic Assessment and Uneventful Live Rotavirus Vaccination Despite Continuous Tofacitinib Exposure In Utero and During Breastfeeding.

Janus kinase (JAK) inhibitors are effective for the treatment of inflammatory bowel disease (IBD). However, this class of medications is not recommended during pregnancy or breastfeeding based on animal data suggesting teratogenesis and recent reports of transmammary transfer after maternal ingestion, raising concerns for immune system development in babies exposed to these drugs. We present the case of a patient with IBD treated with a JAK inhibitor who decided to continue the medication throughout her pregnancy and during breastfeeding. This is the first reported case of a detailed immunologic profile in a baby exposed to tofacitinib in utero and during lactation. A 30-year-old female with ulcerative colitis with previous exposure to vedolizumab and infliximab achieved complete remission with tofacitinib therapy. The patient became pregnant after 5 months of JAK inhibitor therapy and decided to continue tofacitinib during pregnancy and while breastfeeding. The patient delivered a healthy offspring with no congenital malformations, a normal detailed immunologic profile, and subsequent safe provision of the live oral rotavirus vaccine. This case highlights the importance of individualized counseling for patients of childbearing age who are candidates for JAK inhibition. Those who are pregnant or breastfeeding with refractory disease may have limited medical therapeutic options. Ongoing effective therapy for IBD resulted in complete disease remission in the mother and favorable outcomes in the infant. Further, an in-depth infant immunological assessment can lead to specific vaccination recommendations in exposed infants.

Effectiveness of Pentavalent Rotavirus Vaccine in Shanghai, China: A Test-Negative Design Study

To evaluate vaccine effectiveness (VE) of a live oral pentavalent rotavirus vaccine (RotaTeq, RV5) among young children in Shanghai, China, via a test-negative design study. We consecutively recruited children visiting a tertiary children's hospital for acute diarrhea from November 2021 to February 2022. Information on clinical data and rotavirus vaccination was collected. Fresh fecal samples were obtained for rotavirus detection and genotyping. To evaluate VE of RV5 against rotavirus gastroenteritis among young children, unconditional logistic regression models were conducted to compare ORs for vaccination between rotavirus-positive cases and test-negative controls. A total of 390 eligible children with acute diarrhea were enrolled, including 45 (11.54%) rotavirus-positive cases and 345 (88.46%) test-negative controls. After excluding 4 cases (8.89%) and 55 controls (15.94%) who had received the Lanzhou lamb rotavirus vaccine, 41 cases (12.39%) and 290 controls (87.61%) were included for the evaluation of RV5 VE. After adjustment for potential confounders, the 3-dose RV5 vaccination showed 85% (95% CI, 50%-95%) VE against mild to moderate rotavirus gastroenteritis among children aged 14 weeks to≤4years and 97% (95% CI, 83%-100%) VE among children aged 14 weeks to≤2years with genotypes G8P8, G9P8, and G2P4 represented 78.95%, 18.42%, and 2.63% of circulation strains, respectively. A 3-dose vaccination of RV5 is highly protective against rotavirus gastroenteritis among young children in Shanghai. The G8P8 genotype prevailled in Shanghai after RV5 introduction.

Investigating association between inflammatory bowel disease and rotavirus vaccination in a paediatric cohort in the UK.

In the UK, the incidence and prevalence of inflammatory bowel disease (IBD) is increasing in paediatric populations. Environmental factors including acute gastroenteritis episodes (AGE) may impact IBD development. Infant rotavirus vaccination has been shown to significantly reduce AGE. This study aims to explore the association between vaccination with live oral rotavirus vaccines and IBD development. A population-based cohort study was used, analysing primary care data from the Clinical Practice Research Datalink Aurum. Participants included children born in the UK from 2010 to 2015, followed from a minimum of 6months old to a maximum of 7years old. The primary outcome was IBD, and the primary exposure was rotavirus vaccination. Cox regression analysis with random intercepts for general practices was undertaken, with adjustment for potential confounding factors. In a cohort of 907,477 children, IBD was recorded for 96 participants with an incidence rate of 2.1 per 100,000 person-years at risk. The univariable analysis hazard ratio (HR) for rotavirus vaccination was 1.45 (95% confidence interval (CI) 0.93-2.28). Adjustment in the multivariable model attenuated the HR to 1.19 (95% CI 0.53-2.69). This study shows no statistically significant association between rotavirus vaccination and development of IBD. However, it provides further evidence for the safety of live rotavirus vaccination.

Potential impact and cost-effectiveness of injectable next-generation rotavirus vaccines in 137 LMICs: a modelling study

ABSTRACT While current live, oral rotavirus vaccines (LORVs) are reducing severe diarrhea everywhere, their effectiveness is lower in high burden settings. Alternative approaches are in advanced stages of clinical development, including injectable next-generation rotavirus vaccine (iNGRV) candidates, which have the potential to better protect children, be combined with existing routine immunizations and be more affordable than current LORVs. In an effort to better understand the real public health value of iNGRVs and to help inform decisions by international agencies, funders, and vaccine manufacturers, we conducted an impact and cost-effectiveness analysis examining 20 rotavirus vaccine use cases. We evaluated several currently licensed LORVs, one neonatal oral NGRV (oNGRV), one iNGRV, and one iNGRV-DTP (iNGRV comprising part of a DTP-containing combination) over a ten-year timeframe in 137 low- and middle-income countries. The most promising use case identified was a high efficacy iNGRV-DTP, predicted to have the lowest vaccine program cost (US$1.4 billion), the highest vaccine benefit (750,000 rotavirus deaths averted, 13 million rotavirus hospital admissions averted, US$ 2.7 billion health-care cost averted), and most favorable cost-effectiveness (cost-saving). iNGRV-DTP vaccine remained the most affordable, safe, and cost-effective option even when it was assumed to have equivalent efficacy to the current LORVs. This study shows that while the development of iNGRVs with superior efficacy to currently licensed LORVs would be ideal, iNGRVs with similar efficacy to LORVs would offer substantial public health value. It also highlights the economic value of accelerating the development of DTP-based combination vaccines that include iNGRV to provide rotavirus protection.

Does Anybody Want an Injectable Rotavirus Vaccine, and Why? Understanding the Public Health Value Proposition of Next-Generation Rotavirus Vaccines.

Routine infant immunization with live, oral rotavirus vaccines (LORVs) has had a major impact on severe gastroenteritis disease. Nevertheless, in high morbidity and mortality settings rotavirus remains an important cause of disease, partly attributable to the sub-optimal clinical efficacy of LORVs in those settings. Regardless of the precise immunological mechanism(s) underlying the diminished efficacy, the introduction of injectable next-generation rotavirus vaccines (iNGRV), currently in clinical development, could offer a potent remedy. In addition to the potential for greater clinical efficacy, precisely how iNGRVs are delivered (multiple doses to young infants; alongside LORVs or as a booster; co-formulated with Diphtheria-Tetanus-Pertussis (DTP)-containing vaccines), their pricing, and their storage and cold chain characteristics could each have major implications on the resultant health outcomes, on cost-effectiveness as well as on product preferences by national stakeholders and healthcare providers. To better understand these implications, we critically assessed whether there is a compelling public health value proposition for iNGRVs based on potential (but still hypothetical) vaccine profiles. Our results suggest that the answer is highly dependent on the specific use cases and potential attributes of such novel vaccines. Notably, co-formulation of iNGRVs with similar or greater efficacy than LORVs with a DTP-containing vaccine, such as DTP-Hib-HepB, scored especially high on potential impact, cost-effectiveness, and strength of preference by national stakeholders and health care providers in lower and middle income countries.

National stakeholder preferences for next-generation rotavirus vaccines: Results from a six-country study

BackgroundCurrently available live, oral rotavirus vaccines (LORVs) have significantly reduced severe rotavirus hospitalizations and deaths worldwide. However, LORVs are not as effective in low- and middle-income countries (LMIC) where rotavirus disease burden is highest. Next-generation rotavirus vaccine (NGRV) candidates in development may have a greater public health impact where they are needed most. The feasibility and acceptability of possible new rotavirus vaccines were explored as part of a larger public health value proposition for injectable NGRVs in LMICs. ObjectiveTo assess national stakeholder preferences for currently available LORVs and hypothetical NGRVs and understand rationales and drivers for stated preferences. MethodsInterviews were conducted with 71 national stakeholders who influence vaccine policy and national programming. Stakeholders from Ghana, Kenya, Malawi, Peru, Senegal, and Sri Lanka were interviewed using a mixed-method guide. Vaccine preferences were elicited on seven vaccine comparisons involving LORVs and hypothetical NGRVs based on information presented comparing the vaccines’ attributes. Reasons for vaccine preference were elicited in open-ended questions, and the qualitative data were analyzed on key preference drivers. ResultsNearly half of the national stakeholders interviewed preferred a highly effective standalone, injectable NGRV over current LORVs. When presented as having similar efficacy to the LORV, however, very few stakeholders preferred the injectable NGRV, even at substantially lower cost. Similarly, a highly effective standalone injectable NGRV was generally not favored over an equally effective oral NGRV following a neonatal-infant schedule, despite higher cost of the neonatal option. An NGRV-DTP-containing combination vaccine was strongly preferred over all other options, whether delivered alone with efficacy similar to current LORVs or co-administered alongside an LORV (LORV + NGRV-DTP) to increase efficacy. ConclusionResults from these national stakeholder interviews provide valuable insights to inform ongoing and future NGRV research and development.

TLR genetic variation is associated with Rotavirus–specific IgA seroconversion in South African Black infants after two doses of Rotarix vaccine

Live oral rotavirus vaccines have significantly reduced rotavirus-related diarrheal morbidity and mortality globally, but low efficacy of these vaccines is observed in low–income countries where disease burden is highest. The biological basis of rotavirus vaccine failure remains unknown but likely includes both microbial and host factors. We investigated associations between 19 candidate SNPs in the TLR3, TLR7, TLR8, DDX58 and IFIH1 genes that play a role in innate immunity, and seroconversion in Black South African infants after vaccination with Rotarix at 6 and 14 weeks of age.Rotavirus-specific IgA antibody titre was measured by ELISA before each vaccine dose and four weeks after the second dose, and seroconversion was defined as a four-fold or greater increase in IgA antibody titre at 18 weeks of age when compared to pre-vaccine titres. A total of 95/138 individuals seroconverted (68.8%) and seroconversion was significantly affected by birthweight (P = 0.010), pre-vaccine IgA and IgG titres (P = 0.0002 and P = 0.007 respectively).rs2159377 SNP in TLR8 was significantly associated with seroconversion in a univariate allelic model (P = 0.015) and was borderline significant in a multivariable logistic regression adjusted for birthweight and pre-vaccine titres (P = 0.071), although these values did not remain significant after Bonferroni correction. A haplotype of six SNPs on the X chromosome across TLR7 and TLR8, including rs179008 and rs5935438 minor alleles, was significantly associated with seroconversion in a univariate model (P = 0.042), but not in a multivariable model or after Bonferroni correction. Epistatic interaction between rs5743305 in TLR3 and rs55789327 in DDX58 was significantly associated with seroconversion (P = 0.034) but a genetic risk score constructed from all 19 minor alleles was not.Our results suggest that TLR variants may influence IgA antibody production and seroconversion to Rotarix vaccine in South Africans. Host genetic variation contributes to the varying immunogenicity of live oral rotavirus vaccines.

Immunogenicity of an oral rotavirus vaccine administered with prenatal nutritional support in Niger: A cluster randomized clinical trial.

BackgroundNutritional status may play a role in infant immune development. To identify potential boosters of immunogenicity in low-income countries where oral vaccine efficacy is low, we tested the effect of prenatal nutritional supplementation on immune response to 3 doses of a live oral rotavirus vaccine.Methods and findingsWe nested a cluster randomized trial within a double-blind, placebo-controlled randomized efficacy trial to assess the effect of 3 prenatal nutritional supplements (lipid-based nutrient supplement [LNS], multiple micronutrient supplement [MMS], or iron–folic acid [IFA]) on infant immune response (n = 53 villages and 1,525 infants with valid serology results: 794 in the vaccine group and 731 in the placebo group). From September 2015 to February 2017, participating women received prenatal nutrient supplement during pregnancy. Eligible infants were then randomized to receive 3 doses of an oral rotavirus vaccine or placebo at 6–8 weeks of age (mean age: 6.3 weeks, 50% female). Infant sera (pre-Dose 1 and 28 days post-Dose 3) were analyzed for anti-rotavirus immunoglobulin A (IgA) using enzyme-linked immunosorbent assay (ELISA). The primary immunogenicity end point, seroconversion defined as ≥3-fold increase in IgA, was compared in vaccinated infants among the 3 supplement groups and between vaccine/placebo groups using mixed model analysis of variance procedures. Seroconversion did not differ by supplementation group (41.1% (94/229) with LNS vs. 39.1% (102/261) with multiple micronutrients (MMN) vs. 38.8% (118/304) with IFA, p = 0.91). Overall, 39.6% (n = 314/794) of infants who received vaccine seroconverted, compared to 29.0% (n = 212/731) of infants who received placebo (relative risk [RR]: 1.36; 95% confidence interval [CI]: 1.18, 1.57, p < 0.001). This study was conducted in a high rotavirus transmission setting. Study limitations include the absence of an immune correlate of protection for rotavirus vaccines, with the implications of using serum anti-rotavirus IgA for the assessment of immunogenicity and efficacy in low-income countries unclear.ConclusionsThis study showed no effect of the type of prenatal nutrient supplementation on immune response in this setting. Immune response varied depending on previous exposure to rotavirus, suggesting that alternative delivery modalities and schedules may be considered to improve vaccine performance in high transmission settings.Trial registrationClinicalTrials.gov NCT02145000.

Role of rotavirus vaccination on G9P[8] rotavirus strain during a seasonal outbreak in Japan

ABSTRACT Although two live oral rotavirus (RV) vaccines, Rotarix and RotaTeq, play a critical role toward reducing disease severity, hospitalization, and death rate in RV infections, regular monitoring of vaccine effectiveness (VE) is yet necessary because the segmented genome structure and reassortment capability of RVs pose considerable threats toward waning VE. In this study, we examined the VE by a test-negative study design against G9P[8]I2 strain during a seasonal outbreak in February–May, 2018, in an outpatient clinic in Kyoto Prefecture, Japan. It remains important because G9P[8]I2 strain remains partially heterotypic to these vaccines and predominating in post-vaccination era. During year-long surveillance, RV infections were detected only from February to May. During this outbreak, 33 (42.3%) children out of 78 with acute gastroenteritis (AGE) remained RV-positive, of which 29 (87.8%) children were infected with G9P[8]I2. Two immunochromatographic (IC) assay kits exhibited 100% sensitivity and specificity to detect G9P[8]I2 strain. Only 23.2% children were found to be vaccinated. Yet, significant VE 69.7% (95% CI: 2.5%-90.6%) was recognized against all RV strains that increased with disease severity. Similar significant VE 71.8% (95% CI: 1%-92%) was determined against G9P[8]I2 strain. The severity score remained substantially low in vaccinated children. Our data reveal that vaccine-preventable G9P[8]I2 strain yet may cause outbreak where vaccination coverage remains low. Thus, this study emphasizes the necessity of global introduction of RV-vaccines in national immunization programs of every country.

Thermostable, Dissolvable Buccal Film Rotavirus Vaccine Is Highly Effective in Neonatal Gnotobiotic Pig Challenge Model.

Difficulties related to storage and transport of currently available live oral rotavirus vaccines can have detrimental consequences on the efficacy of the vaccines. Thus, there is a great need for thermostable vaccines that can eliminate the necessity for cold chain storage or reconstitution before administration. In this study, we developed a dissolvable oral polymeric film comprised of a live attenuated thermostable tetravalent rhesus-human reassortant rotavirus vaccine (RRV-TV) powder and antacid (CaCO3). Immunogenicity and protective efficacy of the vaccine after buccal delivery was evaluated in the gnotobiotic pig model of human rotavirus (HRV) infection and diarrhea. Two doses of the vaccine were highly immunogenic and conferred strong protection against virus shedding and diarrhea upon challenge with a high dose of a virulent G1 HRV in gnotobiotic pigs. Those pigs vaccinated with the preserved film vaccine had significantly delayed onset of diarrhea; reduced duration and area under the curve of diarrhea; delayed onset of fecal virus shedding; and reduced duration and peak of fecal virus shedding titers compared to pigs in both the placebo and the reconstituted liquid oral RRV-TV vaccine groups. Associated with the strong protection, high titers of serum virus neutralization antibodies against each of the four RRV-TV mono-reassortants and G1 HRV-specific serum IgA and IgG antibodies, as well as intestinal IgA antibodies, were induced by the preserved film vaccine. These results demonstrated the effectiveness of our thermostable buccal film rotavirus vaccine and warrant further investigation into the promise of the novel technology in addressing drawbacks of the current live oral HRV vaccines.

Meta-analysis of the effectiveness of pentavalent live oral vaccine for the prevention of severe forms of rotavirus gastroenteritis in children

Rotavirus infection is ubiquitously distributed and represents a global public health problem. Some studies showed that vaccination with pentavalent oral live vaccine was effective in prevention of severe forms of rotavirus gastroenteritis among children up to 3 years of age. Previous randomized placebo-controlled studies assessing this issue were repeatedly conducted. However, due to the features of the epidemiology of pediatric rotavirus infection in Russia, a metaanalysis was conducted in the risk group — children under the age of 3 years by administering a full vaccination course for a single vaccine registered in the Russian Federation. A search was performed by two independent reviewers covering 1994 to February 2019, without restrictions on language, in five databases on medical and biological publications: Russian Science Citation Index, PubMed, Web of Science, MEDLINE, Scopus, and in contents of thematic journals and bibliographic lists. The meta-analysis included multicenter randomized controlled trials comparing the efficacy of placebo and completed full vaccination course with pentavalent live oral rotavirus vaccine in children under 3 years of age. The primary endpoint of the study was the incidence of severe gastroenteritis among children according to the Vesikari evaluation system. Data processing and generation of forest-plots to evaluate summarized results were carried out by the RevMan 5.3 free software distributed on the Cochrane Community website. The implementation of the “trim and fill” method was performed by using Stata 14.2 software. The meta-analysis consisted of 7 original publications performed as multicenter randomized, placebo-controlled double-blind studies. In the experimental and control group there were enrolled 19,384 and 19,425 subjects, respectively. Three-dose vaccination protocol markedly reduced a risk of infection with severe rotavirus gastroenteritis in the experimental group compared to control group, the odds ratio was 0.34 [95%, CI 0.19—0.60]. Cluster analysis also confirmed the protective effect of the full vaccination course. Group assessment of the vaccination effectiveness against rotavirus infection in countries of Africa and Southeast Asia showed significant protection, the odds ratio was 0.60 [95%, CI 0.52—0.70]. While evaluating the effectiveness of vaccination against rotavirus infection in Finland, the odds ratio was set at the level of statistical significance and reached 0.07 [95%, CI 0.04—0.11]. Thus, a full vaccination course with pentavalent live oral vaccine against rotavirus infection lowers a risk of developing severe rotavirus gastroenteritis in young children.

Associations of Intussusception With Adenovirus, Rotavirus, and Other Pathogens: A Review of the Literature.

Intussusception is the leading cause of acute intestinal obstruction in infants. Intussusception is mostly idiopathic, but infectious pathogens are sometimes implicated. In addition, live oral rotavirus vaccines have been associated with intussusception. We searched the literature published between January 1, 1990, and March 16, 2020, to describe the association between intussusception among infants and young children and various pathogens, particularly adenovirus and wild rotavirus. We tallied the number of evaluations reporting a statistically significant positive association, no association and a protective association by pathogen, using any statistical method. We also calculated the median reported odds ratios (OR) of intussusception with adenovirus and rotavirus. We identified 3793 records on intussusception from the literature; 17 evaluations from 15 countries that evaluated 52 pathogens were included in the analysis. All 14 evaluations of adenovirus reported a statistically significant positive association with intussusception; the median OR from 9 evaluations was 3.7 (interquartile range, 3.3, 8.2). Nine of 12 evaluations assessing rotavirus found no statistically significant association, 1 found a positive association and 2 reported a protective effect; the median OR from 12 evaluations was 0.9 (interquartile range, 0.2, 1.8). No consistent relationship was observed between any other pathogens and intussusception. We documented a consistent association of intussusception with adenovirus, but no relationship between wild-type rotavirus and intussusception. Future research should focus on better understanding the mechanisms of intussusception with infectious pathogens, including following a rotavirus vaccination.

LAP+ Cells Modulate Protection Induced by Oral Vaccination with Rhesus Rotavirus in a Neonatal Mouse Model.

Transforming growth factor β (TGF-β) has been shown to play a role in immunity against different pathogens in vitro and against parasites in vivo However, its role in viral infections in vivo is incompletely understood. Using a neonatal mouse model of heterologous rhesus rotavirus (RV) vaccination, we show that the vaccine induced rotavirus-specific CD4 T cells, the majority of which lacked expression of KLRG1 or CD127, and a few regulatory rotavirus-specific CD4 T cells that expressed surface latency-associated peptide (LAP)-TGF-β. In these mice, inhibiting TGF-β, with both a neutralizing antibody and an inhibitor of TGF-β receptor signaling (activin receptor-like kinase 5 inhibitor [ALK5i]), did not change the development or intensity of the mild diarrhea induced by the vaccine, the rotavirus-specific T cell response, or protection against a subsequent challenge with a murine EC-rotavirus. However, mice treated with anti-LAP antibodies had improved protection after a homologous EC-rotavirus challenge, compared with control rhesus rotavirus-immunized mice. Thus, oral vaccination with a heterologous rotavirus stimulates regulatory RV-specific CD4 LAP-positive (LAP+) T cells, and depletion of LAP+ cells increases vaccine-induced protection.IMPORTANCE Despite the introduction of several live attenuated animal and human rotaviruses as efficient oral vaccines, rotaviruses continue to be the leading etiological agent for diarrhea mortality among children under 5 years of age worldwide. Improvement of these vaccines has been partially delayed because immunity to rotaviruses is incompletely understood. In the intestine (where rotavirus replicates), regulatory T cells that express latency-associated peptide (LAP) play a prominent role, which has been explored for many diseases but not specifically for infectious agents. In this paper, we show that neonatal mice given a live oral rotavirus vaccine develop rotavirus-specific LAP+ T cells and that depletion of these cells improves the efficiency of the vaccine. These findings may prove useful for the design of strategies to improve rotavirus vaccines.

Efficacy of live oral rotavirus vaccines by duration of follow-up: a meta-regression of randomised controlled trials

SummaryBackgroundThe duration of protection offered by rotavirus vaccines varies across the world, and this variation is important to understanding and predicting the effects of the vaccines. There is now a large body of evidence on the efficacy of live oral rotavirus vaccines in different settings, but these data have never been synthesised to obtain robust estimates of efficacy by duration of follow-up. Our aim is to estimate the efficacy of live oral rotavirus vaccines at each point during follow-up and by mortality stratum.MethodsIn our meta-regression study, we identified all randomised controlled trials of rotavirus vaccines published until April 4, 2018, using the results of a Cochrane systematic review, and cross checked these studies against those identified by another systematic review. We excluded trials that were based on special populations, trials without an infant schedule, and trials without clear reporting of numbers of enrolled infants and events in different periods of follow-up. For all reported periods of follow-up, we extracted the mean duration of follow-up (time since administration of the final dose of rotavirus vaccination), the number of enrolled infants, and case counts for rotavirus-positive severe gastroenteritis in both non-vaccinated and vaccinated groups. We used a Bayesian hierarchical Poisson meta-regression model to estimate the pooled cumulative vaccine efficacy (VE) and its waning with time for three mortality strata. We then converted these VE estimates into instantaneous VE (iVE).FindingsIn settings with low mortality (15 observations), iVE pooled for infant schedules of Rotarix and RotaTeq was 98% (95% credibility interval 93–100) 2 weeks following the final dose of vaccination and 94% (87–98) after 12 months. In medium-mortality settings (11 observations), equivalent estimates were 82% (74–92) after 2 weeks and 77% (67–84) after 12 months. In settings with high mortality (24 observations), there were five different vaccines with observation points for infant schedules. The pooled iVE was 66% (48–81) after 2 weeks of follow-up and 44% (27–59) after 12 months.InterpretationRotavirus vaccine efficacy is lower and wanes more rapidly in high-mortality settings than in low-mortality settings, but the earlier peak age of disease in high-mortality settings means that live oral rotavirus vaccines are still likely to provide substantial benefit.FundingBill & Melinda Gates Foundation.

Lack of immune interference between inactivated polio vaccine and inactivated rotavirus vaccine co-administered by intramuscular injection in two animal species

A parenteral inactivated rotavirus vaccine (IRV) in development could address three problems with current live oral rotavirus vaccines (ORV): their lower efficacy in low and middle-income countries (LMICs), lingering concerns about their association with intussusception, and their requirement for a separate supply chain with large volume cold storage. Adding a new parenteral IRV to the current schedule of childhood immunizations would be more acceptable if it could be combined with another injectable vaccine such as inactivated polio vaccine (IPV). Current plans for polio eradication call for phasing out oral polio vaccine (OPV) and transitioning to IPV, initially in LMICs as a single dose booster after two doses of OPV and ultimately as a two dose schedule. Today in many LMICs, IPV is administered as a standalone vaccine, which involves a separate cold chain and is relatively costly. We therefore tested in two animal models formulations of IPV with IRV to determine whether co-administration might interfere with the immune response to each product and spare antigen dose for both vaccines. Our results demonstrate that IRV when adjuvanted with alum and administered alone or in combination with IPV did not impair the immune responses to either rotavirus or poliovirus serotypes 1, 2 and 3. Similarly, IPV when formulated and administered alone or together with IRV induced comparable levels of neutralizing antibody to poliovirus type 1, 2 and 3. Furthermore, comparable antibody titers were observed in animals vaccinated with low, middle or high dose of IPV or IRV in combination. This dose sparing and the lack of interference between IPV and IRV administered together represent another step to support the further development of this novel combination vaccine for children.

The future control of rotavirus disease: Can live oral vaccines alone solve the rotavirus problem?

Live oral rotavirus (RV) vaccines used worldwide are most effective in reducing diarrheal hospitalizations from RV in high income countries and least effective in low income countries where RV remains a prime cause of death in children. Research has failed to fully explain the reason for this difference of efficacy for RV vaccines, an observation made with other live oral vaccines for polio, cholera and typhoid fever. Use of parenteral vaccines have been successful in overcoming this problem for both polio and typhoid and parenteral RV vaccines are now in development. This approach should be pursued for rotavirus vaccine as well because in low income countries where oral RV vaccines have been introduced and are only partially effective, RV remains the most common cause of diarrhea in children under 5 years. The ultimate control of RV diarrheal will likely require both oral and parenteral vaccines.

Rotavirus Vaccines: Effectiveness, Safety, and Future Directions

Rotavirus is the leading cause of diarrheal death among children<5years old worldwide, estimated to have caused~215,000 deaths in 2013. Prior to rotavirus vaccine implementation,>65% of children had at least one rotavirus diarrhea illness by 5years of age and rotavirus accounted for>40% of all-cause diarrhea hospitalizations globally. Two live, oral rotavirus vaccines have been implemented nationally in>100 countries since 2006 and their use has substantially reduced the burden of severe diarrheal illness in all settings. Vaccine efficacy and effectiveness estimates suggest there is a gradient in vaccine performance between low child-mortality countries (>90%) and medium and high child-mortality countries (57-75%). Additionally, an increased risk of intussusception (~1-6 per 100,000 vaccinated infants) following vaccination has been documented in some countries, but this is outweighed by the large benefits of vaccination. Two additional live, oral rotavirus vaccines were recently licensed and these have improved on some programmatic limitations of earlier vaccines, such as heat stability, cost, and cold-chain footprint. Non-replicating rotavirus vaccines that are parenterally administered are in clinical testing, and these have the potential to reduce the performance differential and safety concerns associated with live oral rotavirus vaccines.