Advances in enteric disease vaccines: from innovation to implementation

The Seventh International Conference on Vaccines for Enteric Diseases Bangkok, Thailand, 6–8 November 2013 Hosting 222 participants from more than 25 countries, the Seventh International Conference on Vaccines for Enteric Diseases (VED 2013) displayed the considerable progress that has been made in recent years towards unraveling the burden and etiology of enteric infections, alongside advances in the development, testing and implementation of vaccines that target them. The pervasive nature of enteric diseases, and the significant morbidity and mortality they account for, underscore the substantial public health benefits achievable through the use of enteric vaccines. A number of key talking points raised during the conference are discussed here, including early experiences with the use of double-mutant heat-labile enterotoxin as an antigen and adjuvant, progress and challenges associated with the implementation of oral cholera vaccines, and the issue of impaired rotavirus vaccine immunogenicity in lower-income countries

Influence of Enteric Infections on Response to Oral Poliovirus Vaccine: A Systematic Review and Meta-analysis

BACKGROUND: The impaired immunogenicity of oral poliovirus vaccine (OPV) in low-income countries has been apparent since the early field trials of this vaccine. Infection with enteropathogens at the time of vaccination may contribute to this phenomenon. However, the relative influence of these infections on OPV performance remains uncertain. METHODS: We conducted a systematic review to examine the impact of concurrent enteric infections on OPV response. Using random-effects models, we assessed the effects of nonpolio enteroviruses (NPEVs) and diarrhea on the odds of seroconversion and/or vaccine virus shedding. RESULTS: We identified 25 trials in which OPV outcomes were compared according to the presence or absence of enteric infections, the majority of which (n = 17) reported only on NPEVs. Concurrent NPEVs significantly reduced the odds of per-dose seroconversion for type 1 poliovirus (odds ratio [OR] 0.44, 95% confidence interval 0.23-0.84), but not type 2 (OR 0.53 [0.19-1.46]) or type 3 (OR 0.56 [0.27-1.12]). A similar reduction, significant for type 1 poliovirus (OR 0.50 [0.28-0.89]), was observed in the odds of vaccine virus shedding among NPEV-infected individuals. Concurrent diarrhea significantly inhibited per-dose seroconversion overall (OR 0.61 [0.38-0.87]). CONCLUSIONS: Our findings are consistent with an inhibitory effect of concurrent enteric infections on OPV response

Comparison of molecular testing strategies for COVID-19 control: a mathematical modelling study

BACKGROUND: WHO has called for increased testing in response to the COVID-19 pandemic, but countries have taken different approaches and the effectiveness of alternative strategies is unknown. We aimed to investigate the potential impact of different testing and isolation strategies on transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We developed a mathematical model of SARS-CoV-2 transmission based on infectiousness and PCR test sensitivity over time since infection. We estimated the reduction in the effective reproduction number (R) achieved by testing and isolating symptomatic individuals, regular screening of high-risk groups irrespective of symptoms, and quarantine of contacts of laboratory-confirmed cases identified through test-and-trace protocols. The expected effectiveness of different testing strategies was defined as the percentage reduction in R. We reviewed data on the performance of antibody tests reported by the Foundation for Innovative New Diagnostics and examined their implications for the use of so-called immunity passports. FINDINGS: If all individuals with symptoms compatible with COVID-19 self-isolated and self-isolation was 100% effective in reducing onwards transmission, self-isolation of symptomatic individuals would result in a reduction in R of 47% (95% uncertainty interval [UI] 32-55). PCR testing to identify SARS-CoV-2 infection soon after symptom onset could reduce the number of individuals needing to self-isolate, but would also reduce the effectiveness of self-isolation (around 10% would be false negatives). Weekly screening of health-care workers and other high-risk groups irrespective of symptoms by use of PCR testing is estimated to reduce their contribution to SARS-CoV-2 transmission by 23% (95% UI 16-40), on top of reductions achieved by self-isolation following symptoms, assuming results are available at 24 h. The effectiveness of test and trace depends strongly on coverage and the timeliness of contact tracing, potentially reducing R by 26% (95% UI 14-35) on top of reductions achieved by self-isolation following symptoms, if 80% of cases and contacts are identified and there is immediate testing following symptom onset and quarantine of contacts within 24 h. Among currently available antibody tests, performance has been highly variable, with specificity around 90% or lower for rapid diagnostic tests and 95-99% for laboratory-based ELISA and chemiluminescent assays. INTERPRETATION: Molecular testing can play an important role in prevention of SARS-CoV-2 transmission, especially among health-care workers and other high-risk groups, but no single strategy will reduce R below 1 at current levels of population immunity. Immunity passports based on antibody tests or tests for infection face substantial technical, legal, and ethical challenges. FUNDING: UK Medical Research Council

Enhancing rotavirus vaccination: a microbial fix?

Oral rotavirus vaccines have consistently underperformed in low-income countries. In this issue of Cell Host & Microbe,Harris et al. (2018b) explore whether vaccine response can be enhanced via antibiotic-mediated modification of the bacterial microbiota

Role of molecular testing in COVID-19 control: a mathematical modelling study

Background: The World Health Organization has called for increased testing in response to COVID-19, but countries have taken different approaches and the effectiveness of alternative strategies is unknown. Methods: We developed a mathematical model of SARS-CoV-2 transmission based on infectiousness and PCR test sensitivity over time since infection. We estimated the reduction in the reproduction number (R) achieved by testing and isolating symptomatic individuals, regular screening of high-risk groups irrespective of symptoms,and quarantine of contacts identified through ‘test-and-trace’ protocols. We reviewed data on the performance of antibody tests reported by the Foundation for Innovative New Diagnostics and examined the potential of ‘immunity passports’. Results: Weekly screening of healthcare workers and other high-riskgroups irrespective of symptoms using PCR is estimated to reduce their contribution to transmissionby 23% (95% uncertainty interval: 16-40%), on top of reductions achieved by self-isolation following symptoms, assuming results are available at 24 hours. The effectiveness of test-and-trace depends strongly on coverage and the timeliness of contact tracing, potentially reducing R by26% (14-35%) if 80% of cases and contactsare identified and there is immediate testing on symptom onset and quarantine of contacts within 24 hours. Immunity passports based on tests for antibody or infection face significant technical, legal and ethical challenges. Interpretation: PCR and antibody testing can play a critical role in prevention of SARS-CoV-2 transmission, especially among healthcare workers and other high-risk groups,but no single strategy will reduce R below 1 at current levels of population immunity

Cessation of exclusive breastfeeding and seasonality, but not small intestinal bacterial overgrowth, are associated with environmental enteric dysfunction: A birth cohort study amongst infants in rural Kenya

Background Environmental Enteric Dysfunction (EED) is a chronic intestinal inflammatory disorder of unclear aetiology prevalent amongst children in low-income settings and associated with stunting. We aimed to characterise development of EED and its putative risk factors amongst rural Kenyan infants. Methods In a birth cohort study in Junju, rural coastal Kenya, between August 2015 and January 2017, 100 infants were each followed for nine months. Breastfeeding status was recorded weekly and anthropometry monthly. Acute illnesses and antibiotics were captured by active and passive surveillance. Intestinal function and small intestinal bacterial overgrowth (SIBO) were assessed by monthly urinary lactulose mannitol (LM) and breath hydrogen tests. Faecal alpha-1-antitrypsin, myeloperoxidase and neopterin were measured as EED biomarkers, and microbiota composition assessed by 16S sequencing. Findings Twenty nine of the 88 participants (33%) that underwent length measurement at nine months of age were stunted (length-for-age Z score <-2). During the rainy season, linear growth was slower and LM ratio was higher. In multivariable models, LM ratio, myeloperoxidase and neopterin increased after cessation of continuous-since-birth exclusive breastfeeding. For LM ratio this only occurred during the rainy season. EED markers were not associated with antibiotics, acute illnesses, SIBO, or gut microbiota diversity. Microbiota diversified with age and was not strongly associated with complementary food introduction or linear growth impairment. Interpretation Our data suggest that intensified promotion of uninterrupted exclusive breastfeeding amongst infants under six months during the rainy season, where rainfall is seasonal, may help prevent EED. Our findings also suggest that therapeutic strategies directed towards SIBO are unlikely to impact on EED in this setting. However, further development of non-invasive diagnostic methods for SIBO is required. Funding This research was funded in part by the Wellcome Trust (Research Training Fellowship to RJC (103376/Z/13/Z)). EPKP was supported by the MRC/DfID Newton Fund (MR/N006259/1). JAB was supported by the MRC/DFiD/Wellcome Trust Joint Global Health Trials scheme (MR/M007367/1) and the Bill & Melinda Gates Foundation (OPP1131320). HHU was supported by the NIHR Oxford Biomedical Research Centre (IS-BRC-1215-20008)

Influence of nonpolio enteroviruses and the bacterial gut microbiota on oral poliovirus vaccine response: A study from south India

Background Oral poliovirus vaccine (OPV) is less immunogenic in low- or middle-income than in high-income countries. We tested whether bacterial and viral components of the intestinal microbiota are associated with this phenomenon. Methods We assessed the prevalence of enteropathogens using TaqMan array cards 14 days before and at vaccination in 704 Indian infants (aged 6–11 months) receiving monovalent type 3 OPV (CTRI/2014/05/004588). Nonpolio enterovirus (NPEV) serotypes were identified by means of VP1 sequencing. In 120 infants, the prevaccination bacterial microbiota was characterized using 16S ribosomal RNA sequencing. Results We detected 56 NPEV serotypes on the day of vaccination. Concurrent NPEVs were associated with a reduction in OPV seroconversion, consistent across species (odds ratio [95% confidence interval], 0.57 [.36–.90], 0.61 [.43–.86], and 0.69 [.41–1.16] for species A, B, and C, respectively). Recently acquired enterovirus infections, detected at vaccination but not 14 days earlier, had a greater interfering effect on monovalent type 3 OPV seroresponse than did persistent infections, with enterovirus detected at both time points (seroconversion in 44 of 127 infants [35%] vs 63 of 129 [49%]; P = .02). The abundance of specific bacterial taxa did not differ significantly according to OPV response, although the microbiota was more diverse in nonresponders at the time of vaccination. Conclusion Enteric viruses have a greater impact on OPV response than the bacterial microbiota, with recent enterovirus infections having a greater inhibitory effect than persistent infections

The effect of probiotics and zinc supplementation on the immune response to oral rotavirus vaccine: A randomized, factorial design, placebo-controlled study among Indian infants

Background 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. Methods Infants 5 weeks 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 (5 mg), probiotic (1010 Lactobacillus rhamnosus GG) or placebo on the immunogenicity of two doses of RV (Rotarix®, GlaxoSmithKline Biologicals) given at 6 and 10 weeks 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 14 weeks of age based on detection of VP6-specific IgA at ≥20 U/ml in previously seronegative infants or a fourfold rise in concentration. Results 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. Conclusions 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

Ethnic differences in the indirect effects of the COVID-19 pandemic on clinical monitoring and hospitalisations for non-COVID conditions in England: a population-based, observational cohort study using the OpenSAFELY platform.

BACKGROUND: The COVID-19 pandemic disrupted healthcare and may have impacted ethnic inequalities in healthcare. We aimed to describe the impact of pandemic-related disruption on ethnic differences in clinical monitoring and hospital admissions for non-COVID conditions in England. METHODS: In this population-based, observational cohort study we used primary care electronic health record data with linkage to hospital episode statistics data and mortality data within OpenSAFELY, a data analytics platform created, with approval of NHS England, to address urgent COVID-19 research questions. We included adults aged 18 years and over registered with a TPP practice between March 1, 2018, and April 30, 2022. We excluded those with missing age, sex, geographic region, or Index of Multiple Deprivation. We grouped ethnicity (exposure), into five categories: White, Asian, Black, Other, and Mixed. We used interrupted time-series regression to estimate ethnic differences in clinical monitoring frequency (blood pressure and Hba1c measurements, chronic obstructive pulmonary disease and asthma annual reviews) before and after March 23, 2020. We used multivariable Cox regression to quantify ethnic differences in hospitalisations related to diabetes, cardiovascular disease, respiratory disease, and mental health before and after March 23, 2020. FINDINGS: Of 33,510,937 registered with a GP as of 1st January 2020, 19,064,019 were adults, alive and registered for at least 3 months, 3,010,751 met the exclusion criteria and 1,122,912 were missing ethnicity. This resulted in 14,930,356 adults with known ethnicity (92% of sample): 86.6% were White, 7.3% Asian, 2.6% Black, 1.4% Mixed ethnicity, and 2.2% Other ethnicities. Clinical monitoring did not return to pre-pandemic levels for any ethnic group. Ethnic differences were apparent pre-pandemic, except for diabetes monitoring, and remained unchanged, except for blood pressure monitoring in those with mental health conditions where differences narrowed during the pandemic. For those of Black ethnicity, there were seven additional admissions for diabetic ketoacidosis per month during the pandemic, and relative ethnic differences narrowed during the pandemic compared to the White ethnic group (Pre-pandemic hazard ratio (HR): 0.50, 95% confidence interval (CI) 0.41, 0.60, Pandemic HR: 0.75, 95% CI: 0.65, 0.87). There was increased admissions for heart failure during the pandemic for all ethnic groups, though highest in those of White ethnicity (heart failure risk difference: 5.4). Relatively, ethnic differences narrowed for heart failure admission in those of Asian (Pre-pandemic HR 1.56, 95% CI 1.49, 1.64, Pandemic HR 1.24, 95% CI 1.19, 1.29) and Black ethnicity (Pre-pandemic HR 1.41, 95% CI: 1.30, 1.53, Pandemic HR: 1.16, 95% CI 1.09, 1.25) compared with White ethnicity. For other outcomes the pandemic had minimal impact on ethnic differences. INTERPRETATION: Our study suggests that ethnic differences in clinical monitoring and hospitalisations remained largely unchanged during the pandemic for most conditions. Key exceptions were hospitalisations for diabetic ketoacidosis and heart failure, which warrant further investigation to understand the causes. FUNDING: LSHTM COVID-19 Response Grant (DONAT15912)