Contribution of vaccination to improved survival and health: modelling 50 years of the Expanded Programme on Immunization.

BACKGROUND: WHO, as requested by its member states, launched the Expanded Programme on Immunization (EPI) in 1974 to make life-saving vaccines available to all globally. To mark the 50-year anniversary of EPI, we sought to quantify the public health impact of vaccination globally since the programme's inception. METHODS: In this modelling study, we used a suite of mathematical and statistical models to estimate the global and regional public health impact of 50 years of vaccination against 14 pathogens in EPI. For the modelled pathogens, we considered coverage of all routine and supplementary vaccines delivered since 1974 and estimated the mortality and morbidity averted for each age cohort relative to a hypothetical scenario of no historical vaccination. We then used these modelled outcomes to estimate the contribution of vaccination to globally declining infant and child mortality rates over this period. FINDINGS: Since 1974, vaccination has averted 154 million deaths, including 146 million among children younger than 5 years of whom 101 million were infants younger than 1 year. For every death averted, 66 years of full health were gained on average, translating to 10·2 billion years of full health gained. We estimate that vaccination has accounted for 40% of the observed decline in global infant mortality, 52% in the African region. In 2024, a child younger than 10 years is 40% more likely to survive to their next birthday relative to a hypothetical scenario of no historical vaccination. Increased survival probability is observed even well into late adulthood. INTERPRETATION: Since 1974 substantial gains in childhood survival have occurred in every global region. We estimate that EPI has provided the single greatest contribution to improved infant survival over the past 50 years. In the context of strengthening primary health care, our results show that equitable universal access to immunisation remains crucial to sustain health gains and continue to save future lives from preventable infectious mortality. FUNDING: WHO.

Epidemiology of Human Seasonal Coronaviruses Among People With Mild and Severe Acute Respiratory Illness in Blantyre, Malawi, 2011-2017.

BACKGROUND: The aim of this study was to characterize the epidemiology of human seasonal coronaviruses (HCoVs) in southern Malawi. METHODS: We tested for HCoVs 229E, OC43, NL63, and HKU1 using real-time polymerase chain reaction (PCR) on upper respiratory specimens from asymptomatic controls and individuals of all ages recruited through severe acute respiratory illness (SARI) surveillance at Queen Elizabeth Central Hospital, Blantyre, and a prospective influenza-like illness (ILI) observational study between 2011 and 2017. We modeled the probability of having a positive PCR for each HCoV using negative binomial models, and calculated pathogen-attributable fractions (PAFs). RESULTS: Overall, 8.8% (539/6107) of specimens were positive for ≥1 HCoV. OC43 was the most frequently detected HCoV (3.1% [191/6107]). NL63 was more frequently detected in ILI patients (adjusted incidence rate ratio [aIRR], 9.60 [95% confidence interval {CI}, 3.25-28.30]), while 229E (aIRR, 8.99 [95% CI, 1.81-44.70]) was more frequent in SARI patients than asymptomatic controls. In adults, 229E and OC43 were associated with SARI (PAF, 86.5% and 89.4%, respectively), while NL63 was associated with ILI (PAF, 85.1%). The prevalence of HCoVs was similar between children with SARI and controls. All HCoVs had bimodal peaks but distinct seasonality. CONCLUSIONS: OC43 was the most prevalent HCoV in acute respiratory illness of all ages. Individual HCoVs had distinct seasonality that differed from temperate settings.

Azithromycin for Bacterial Watery Diarrhea: A Reanalysis of the AntiBiotics for Children With Severe Diarrhea (ABCD) Trial Incorporating Molecular Diagnostics.

BACKGROUND: Bacterial pathogens cause substantial diarrhea morbidity and mortality among children living in endemic settings, yet antimicrobial treatment is only recommended for dysentery or suspected cholera. METHODS: AntiBiotics for Children with severe Diarrhea was a 7-country, placebo-controlled, double-blind efficacy trial of azithromycin in children 2-23 months of age with watery diarrhea accompanied by dehydration or malnutrition. We tested fecal samples for enteric pathogens utilizing quantitative polymerase chain reaction to identify likely and possible bacterial etiologies and employed pathogen-specific cutoffs based on genomic target quantity in previous case-control diarrhea etiology studies to identify likely and possible bacterial etiologies. RESULTS: Among 6692 children, the leading likely etiologies were rotavirus (21.1%), enterotoxigenic Escherichia coli encoding heat-stable toxin (13.3%), Shigella (12.6%), and Cryptosporidium (9.6%). More than one-quarter (1894 [28.3%]) had a likely and 1153 (17.3%) a possible bacterial etiology. Day 3 diarrhea was less common in those randomized to azithromycin versus placebo among children with a likely bacterial etiology (risk difference [RD]likely, -11.6 [95% confidence interval {CI}, -15.6 to -7.6]) and possible bacterial etiology (RDpossible, -8.7 [95% CI, -13.0 to -4.4]) but not in other children (RDunlikely, -0.3% [95% CI, -2.9% to 2.3%]). A similar association was observed for 90-day hospitalization or death (RDlikely, -3.1 [95% CI, -5.3 to -1.0]; RDpossible, -2.3 [95% CI, -4.5 to -.01]; RDunlikely, -0.6 [95% CI, -1.9 to .6]). The magnitude of risk differences was similar among specific likely bacterial etiologies, including Shigella. CONCLUSIONS: Acute watery diarrhea confirmed or presumed to be of bacterial etiology may benefit from azithromycin treatment. CLINICAL TRIALS REGISTRATION: NCT03130114.

Cost-effectiveness analysis of typhoid conjugate vaccines in an outbreak setting: a modeling study.

BACKGROUND: Several prolonged typhoid fever epidemics have been reported since 2010 throughout eastern and southern Africa, including Malawi, caused by multidrug-resistant Salmonella Typhi. The World Health Organization recommends the use of typhoid conjugate vaccines (TCVs) in outbreak settings; however, current data are limited on how and when TCVs might be introduced in response to outbreaks. METHODOLOGY: We developed a stochastic model of typhoid transmission fitted to data from Queen Elizabeth Central Hospital in Blantyre, Malawi from January 1996 to February 2015. We used the model to evaluate the cost-effectiveness of vaccination strategies over a 10-year time horizon in three scenarios: (1) when an outbreak is likely to occur; (2) when an outbreak is unlikely to occur within the next ten years; and (3) when an outbreak has already occurred and is unlikely to occur again. We considered three vaccination strategies compared to the status quo of no vaccination: (a) preventative routine vaccination at 9 months of age; (b) preventative routine vaccination plus a catch-up campaign to 15 years of age; and (c) reactive vaccination with a catch-up campaign to age 15 (for Scenario 1). We also explored variations in outbreak definitions, delays in implementation of reactive vaccination, and the timing of preventive vaccination relative to the outbreak. RESULTS: Assuming an outbreak occurs within 10 years, we estimated that the various vaccination strategies would prevent a median of 15-60% of disability-adjusted life-years (DALYs). Reactive vaccination was the preferred strategy for WTP values of $0-300 per DALY averted. For WTP values > $300, introduction of preventative routine TCV immunization with a catch-up campaign was the preferred strategy. Routine vaccination with a catch-up campaign was cost-effective for WTP values above $890 per DALY averted if no outbreak occurs and > $140 per DALY averted if implemented after the outbreak has already occurred. CONCLUSIONS: Countries for which the spread of antimicrobial resistance is likely to lead to outbreaks of typhoid fever should consider TCV introduction. Reactive vaccination can be a cost-effective strategy, but only if delays in vaccine deployment are minimal; otherwise, introduction of preventive routine immunization with a catch-up campaign is the preferred strategy.

Invasiveness potential of pneumococcal serotypes in children after introduction of PCV13 in Blantyre, Malawi.

INTRODUCTION: The introduction of PCV13 to the Malawi infant immunization schedule in 2011 has been associated with reduced disease from Streptococcus pneumoniae. Improved understanding of serotypes with high invasive potential can guide future vaccination interventions. We aimed to estimate pneumococcal serotypes associated with acute respiratory infection (ARI) and invasive pneumococcal disease (IPD) in hospitalized children in Blantyre, Malawi. METHODS: We analysed data from healthy children under 5 years in the community in Blantyre and children admitted to Queen Elizabeth Central Hospital with ARI between 2015 and 2018. Nasopharyngeal swabs from children were tested for S. pneumoniae and serotyped by latex agglutination if positive. We analysed culture-positive blood and cerebrospinal fluid samples from admitted children between 2012 and 2018 to identify cases of IPD after the introduction of PCV13. We calculated the age-adjusted odds ratio (OR) of carriage for S. pneumoniae vaccine serotypes (VT) comparing those with ARI to healthy children. We also calculated age-adjusted ORs comparing serotypes causing IPD to carriage in the community with OR > 1 indicating high invasive potential. RESULTS: Serotypes 5 (OR 24.73 [95% CI 7.90-78.56] p < 0.001), 1 (OR 23.38 [95% CI 9.75-56.06] p < 0.001), and 6B (OR 4.73 [95% CI 1.66-11.64] p = 0.001) had high invasive potential. Serotype 6B was no longer significant (OR 1.34 [95% CI 0.07-6.87] p = 0.777) in a sensitivity analysis accounting for year of recruitment. The prevalence of S. pneumoniae carriage in the community was 72.6% [95% CI 71.3-74.0] (3078/4238) and 23.4% (719/3078) of positive community samples were VT. The carriage prevalence in those hospitalised with ARI was 45.5% [95% CI 42.1-48.9] (389/855) and 43.8% of hospital attendees reported antibiotic use prior to admission. We did not identify significant associations with carriage of any serotypes in those with ARI. CONCLUSIONS: Pneumococcal serotypes 5 and 1 are associated with high invasive potential. Despite high community pneumococcal carriage, pre-hospital antibiotic usage likely reduces pneumococcal detection among children admitted in this setting and further research is needed to investigate serotypes associated with ARI. Data from this study can guide future preventative vaccination strategies in Malawi.

Hepatitis B Vaccination Impact and the Unmet Need for Antiviral Treatment in Blantyre, Malawi.

BACKGROUND: Hepatitis B is the leading cause of cirrhosis and liver cancer in sub-Saharan Africa. To reduce mortality, antiviral treatment programs are needed. We estimated prevalence, vaccine impact, and need for antiviral treatment in Blantyre, Malawi. METHODS: We conducted a household study in 2016-2018. We selected individuals from a census using random sampling and estimated age-sex-standardized hepatitis B surface antigen (HBsAg) seroprevalence. Impact of infant hepatitis B vaccination was estimated by binomial log-linear regression comparing individuals born before and after vaccine implementation. In HBsAg-positive adults, eligibility for antiviral therapy was assessed. RESULTS: Of 97386 censused individuals, 6073 (median age 18 years; 56.7% female) were sampled. HBsAg seroprevalence was 5.1% (95% confidence interval [CI], 4.3%-6.1%) among adults and 0.3% (95% CI, .1%-.6%) among children born after vaccine introduction. Estimated vaccine impact was 95.8% (95% CI, 70.3%-99.4%). Of HBsAg-positive adults, 26% were HIV-positive. Among HIV-negative individuals, 3%, 6%, and 9% were eligible for hepatitis B treatment by WHO, European, and American hepatology association criteria, respectively. CONCLUSIONS: Infant HBV vaccination has been highly effective in reducing HBsAg prevalence in urban Malawi. Up to 9% of HBsAg-positive HIV-negative adults are eligible, but have an unmet need, for antiviral therapy.

Antibody-Mediated Immunogenicity Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Following Priming, Boosting, and Hybrid Immunity: Insights From 11 Months of Follow-up of a Healthcare Worker Cohort in Israel, December 2020-October 2021.

BACKGROUND: We determined circulating anti-S severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) antibody titers in a vaccinated healthcare workers (HCWs) cohort from Northern Israel in the 11 months following primary vaccination according to age, ethnicity, and previous infection status. METHODS: All consenting HCWs were invited to have their IgG levels measured before vaccination and at 6 subsequent timepoints using a quantitative S1/S2 IgG assay. All HCWs with suspected coronavirus disease 2019 (COVID-19) were polymerase chain reaction (PCR) tested. We described trends in circulating IgG geometric mean concentration (GMC) by age, ethnicity, timing of boosting, and previous infection status and compared strata using Kruskall-Wallis tests. RESULTS: Among 985 vaccinated HCWs, IgG titers between 1 month post 2nd dose to pre-boosting gradually decreased in all age groups. Younger or previously infected individuals had higher initial post-vaccination IgG levels (P < .001 in both cases); differences substantially decreased or disappeared at 7-9 months, before boosting. The proportion of individuals infected prior to initiating vaccination and re-infected after dose 1 was comparable to the proportion of breakthrough infection post-dose 2 in those not previously infected (4.2 vs 4.7%). Pre-infection IgG levels in the 40 participants with breakthrough infection after dose 2 were similar to levels measured at the same timepoint in vaccinated HCWs who remained uninfected (P > .3). Post-dose3 IgG levels were more than 10-fold those 1 month post-dose 2. CONCLUSIONS: Immunity waned in all age groups and previously infected individuals, reversed by boosting. IgG titers decrease and reinfections in individuals with hybrid immunity (infection + vaccination) suggests they may also require further doses. Our study also highlights the difficulty in determining protective IgG levels.

Plasma Rotavirus-specific IgA and Risk of Rotavirus Vaccine Failure in Infants in Malawi.

BACKGROUND: Rotavirus vaccine efficacy is reduced in low-income populations, but efforts to improve vaccine performance are limited by lack of clear correlates of protection. Although plasma rotavirus (RV)-specific immunoglobulin A (IgA) appears strongly associated with protection against rotavirus gastroenteritis in high-income countries, weaker association has been observed in low-income countries. We tested the hypothesis that lower RV-specific IgA is associated with rotavirus vaccine failure in Malawian infants. METHODS: In a case-control study, we recruited infants presenting with severe rotavirus gastroenteritis following monovalent oral rotavirus vaccination (RV1 vaccine failures). Conditional logistic regression was used to determine the odds of rotavirus seronegativity (RV-specific IgA < 20 U/mL) in these cases compared 1:1 with age-matched, vaccinated, asymptomatic community controls. Plasma RV-specific IgA was determined by enzyme-linked immunosorbent assay for all participants at recruitment, and for cases at 10 days after symptom onset. Rotavirus infection and genotype were determined by antigen testing and reverse transcription-polymerase chain reaction, respectively. RESULTS: In 116 age-matched pairs, infants with RV1 vaccine failure were more likely to be RV-specific IgA seronegative than controls: odds ratio, 3.1 (95% confidence interval [CI], 1.6-5.9), P=.001. In 60 infants with convalescent serology, 42/45 (93%; 95% CI. 81-98) infants seronegative at baseline became seropositive. Median rise in RV-specific IgA concentration following acute infection was 112.8 (interquartile range, 19.1-380.6)-fold. CONCLUSIONS: In this vaccinated population with high residual burden of rotavirus disease, RV1 vaccine failure was associated with lower RV-specific IgA, providing further evidence of RV-specific IgA as a marker of protection. Robust convalescent RV-specific IgA response in vaccine failures suggests differences in wild-type and vaccine-induced immunity, which informs future vaccine development.

Chatbot-Delivered COVID-19 Vaccine Communication Message Preferences of Young Adults and Public Health Workers in Urban American Communities: Qualitative Study.

BACKGROUND: Automated conversational agents, or chatbots, have a role in reinforcing evidence-based guidance delivered through other media and offer an accessible, individually tailored channel for public engagement. In early-to-mid 2021, young adults and minority populations disproportionately affected by COVID-19 in the United States were more likely to be hesitant toward COVID-19 vaccines, citing concerns regarding vaccine safety and effectiveness. Successful chatbot communication requires purposive understanding of user needs. OBJECTIVE: We aimed to review the acceptability of messages to be delivered by a chatbot named VIRA from Johns Hopkins University. The study investigated which message styles were preferred by young, urban-dwelling Americans as well as public health workers, since we anticipated that the chatbot would be used by the latter as a job aid. METHODS: We conducted 4 web-based focus groups with 20 racially and ethnically diverse young adults aged 18-28 years and public health workers aged 25-61 years living in or near eastern-US cities. We tested 6 message styles, asking participants to select a preferred response style for a chatbot answering common questions about COVID-19 vaccines. We transcribed, coded, and categorized emerging themes within the discussions of message content, style, and framing. RESULTS: Participants preferred messages that began with an empathetic reflection of a user concern and concluded with a straightforward, fact-supported response. Most participants disapproved of moralistic or reasoning-based appeals to get vaccinated, although public health workers felt that such strong statements appealing to communal responsibility were warranted. Responses tested with humor and testimonials did not appeal to the participants. CONCLUSIONS: To foster credibility, chatbots targeting young people with vaccine-related messaging should aim to build rapport with users by deploying empathic, reflective statements, followed by direct and comprehensive responses to user queries. Further studies are needed to inform the appropriate use of user-customized testimonials and humor in the context of chatbot communication.

Duration and Density of Fecal Rotavirus Shedding in Vaccinated Malawian Children With Rotavirus Gastroenteritis.

Quantifying rotavirus shedding among vaccinated individuals will aid understanding of vaccine indirect effects. Serial stool samples were collected from 196 children who presented with rotavirus gastroenteritis to health facilities in Blantyre, Malawi, and were tested for rotavirus using a VP6 semi-quantitative, real-time polymerase chain reaction. The median duration of fecal shedding was 28 days (95% CI, 19-28). The median copy numbers for peak shedding were 1.99 × 107 (interquartile range, 3.39 × 106 to 6.37 × 107). The fecal viral load was positively associated with disease severity and negatively associated with serum anti-rotavirus immunoglobin A. High and persistent rotavirus shedding among vaccinated children with breakthrough disease may contribute to ongoing transmission in this setting.

Early Signals of Vaccine-driven Perturbation Seen in Pneumococcal Carriage Population Genomic Data.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) have reduced pneumococcal diseases globally. Pneumococcal genomic surveys elucidate PCV effects on population structure but are rarely conducted in low-income settings despite the high disease burden. METHODS: We undertook whole-genome sequencing (WGS) of 660 pneumococcal isolates collected through surveys from healthy carriers 2 years from 13-valent PCV (PCV13) introduction and 1 year after rollout in northern Malawi. We investigated changes in population structure, within-lineage serotype dynamics, serotype diversity, and frequency of antibiotic resistance (ABR) and accessory genes. RESULTS: In children <5 years of age, frequency and diversity of vaccine serotypes (VTs) decreased significantly post-PCV, but no significant changes occurred in persons ≥5 years of age. Clearance of VT serotypes was consistent across different genetic backgrounds (lineages). There was an increase of nonvaccine serotypes (NVTs)-namely 7C, 15B/C, and 23A-in children <5 years of age, but 28F increased in both age groups. While carriage rates have been recently shown to remain stable post-PCV due to replacement serotypes, there was no change in diversity of NVTs. Additionally, frequency of intermediate-penicillin-resistant lineages decreased post-PCV. Although frequency of ABR genes remained stable, other accessory genes, especially those associated with mobile genetic element and bacteriocins, showed changes in frequency post-PCV. CONCLUSIONS: We demonstrate evidence of significant population restructuring post-PCV driven by decreasing frequency of vaccine serotypes and increasing frequency of few NVTs mainly in children under 5. Continued surveillance with WGS remains crucial to fully understand dynamics of the residual VTs and replacement NVT serotypes post-PCV.

Predictive value of pulse oximetry for mortality in infants and children presenting to primary care with clinical pneumonia in rural Malawi: A data linkage study.

BACKGROUND: The mortality impact of pulse oximetry use during infant and childhood pneumonia management at the primary healthcare level in low-income countries is unknown. We sought to determine mortality outcomes of infants and children diagnosed and referred using clinical guidelines with or without pulse oximetry in Malawi. METHODS AND FINDINGS: We conducted a data linkage study of prospective health facility and community case and mortality data. We matched prospectively collected community health worker (CHW) and health centre (HC) outpatient data to prospectively collected hospital and community-based mortality surveillance outcome data, including episodes followed up to and deaths within 30 days of pneumonia diagnosis amongst children 0-59 months old. All data were collected in Lilongwe and Mchinji districts, Malawi, from January 2012 to June 2014. We determined differences in mortality rates using <90% and <93% oxygen saturation (SpO2) thresholds and World Health Organization (WHO) and Malawi clinical guidelines for referral. We used unadjusted and adjusted (for age, sex, respiratory rate, and, in analyses of HC data only, Weight for Age Z-score [WAZ]) regression to account for interaction between SpO2 threshold (pulse oximetry) and clinical guidelines, clustering by child, and CHW or HC catchment area. We matched CHW and HC outpatient data to hospital inpatient records to explore roles of pulse oximetry and clinical guidelines on hospital attendance after referral. From 7,358 CHW and 6,546 HC pneumonia episodes, we linked 417 CHW and 695 HC pneumonia episodes to 30-day mortality outcomes: 16 (3.8%) CHW and 13 (1.9%) HC patients died. SpO2 thresholds of <90% and <93% identified 1 (6%) of the 16 CHW deaths that were unidentified by integrated community case management (iCCM) WHO referral protocol and 3 (23%) and 4 (31%) of the 13 HC deaths, respectively, that were unidentified by the integrated management of childhood illness (IMCI) WHO protocol. Malawi IMCI referral protocol, which differs from WHO protocol at the HC level and includes chest indrawing, identified all but one of these deaths. SpO2 < 90% predicted death independently of WHO danger signs compared with SpO2 ≥ 90%: HC Risk Ratio (RR), 9.37 (95% CI: 2.17-40.4, p = 0.003); CHW RR, 6.85 (1.15-40.9, p = 0.035). SpO2 < 93% was also predictive versus SpO2 ≥ 93% at HC level: RR, 6.68 (1.52-29.4, p = 0.012). Hospital referrals and outpatient episodes with referral decision indications were associated with mortality. A substantial proportion of those referred were not found admitted in the inpatients within 7 days of referral advice. All 12 deaths in 73 hospitalised children occurred within 24 hours of arrival in the hospital, which highlights delay in appropriate care seeking. The main limitation of our study was our ability to only match 6% of CHW episodes and 11% of HC episodes to mortality outcome data. CONCLUSIONS: Pulse oximetry identified fatal pneumonia episodes at HCs in Malawi that would otherwise have been missed by WHO referral guidelines alone. Our findings suggest that pulse oximetry could be beneficial in supplementing clinical signs to identify children with pneumonia at high risk of mortality in the outpatient setting in health centres for referral to a hospital for appropriate management.

Evaluation of Pneumococcal Serotyping of Nasopharyngeal-Carriage Isolates by Latex Agglutination, Whole-Genome Sequencing (PneumoCaT), and DNA Microarray in a High-Pneumococcal-Carriage-Prevalence Population in Malawi.

Accurate assessment of the serotype distribution associated with pneumococcal colonization and disease is essential for evaluating and formulating pneumococcal vaccines and for informing vaccine policy. For this reason, we evaluated the concordance between pneumococcal serotyping results by latex agglutination, whole-genome sequencing (WGS) with PneumoCaT, and DNA microarray for samples from community carriage surveillance in Blantyre, Malawi. Nasopharyngeal swabs were collected according to WHO recommendations between 2015 and 2017 by using stratified random sampling among study populations. Participants included healthy children 3 to 6 years old (vaccinated with the 13-valent pneumococcal conjugate vaccine [PCV13] as part of the Expanded Program on Immunization [EPI]), healthy children 5 to 10 years old (age-ineligible for PCV13), and HIV-infected adults (18 to 40 years old) on antiretroviral therapy (ART). For phenotypic serotyping, we used a 13-valent latex kit (Statens Serum Institut [SSI], Denmark). For genomic serotyping, we applied the PneumoCaT pipeline to whole-genome sequence libraries. For molecular serotyping by microarray, we used the BUGS Bioscience Senti-SP microarray. A total of 1,347 samples were analyzed. Concordance was 90.7% (95% confidence interval [CI], 89.0 to 92.2%) between latex agglutination and PneumoCaT, 95.2% (95% CI, 93.9 to 96.3%) between latex agglutination and the microarray, and 96.6% (95% CI, 95.5 to 97.5%) between the microarray and PneumoCaT. By detecting additional vaccine serotype (VT) pneumococci carried at low relative abundances (median, 8%), the microarray increased VT detection by 31.5% over that by latex serotyping. To conclude, all three serotyping methods were highly concordant in identifying dominant serotypes. Latex serotyping is accurate in identifying vaccine serotypes and requires the least expertise and resources for field implementation and analysis. However, WGS, which adds population structure, and microarray, which adds multiple-serotype carriage, should be considered at regional reference laboratories for investigating the importance of vaccine serotypes at low relative abundances in transmission and disease.

Heterogeneous susceptibility to rotavirus infection and gastroenteritis in two birth cohort studies: Parameter estimation and epidemiological implications.

Cohort studies, randomized trials, and post-licensure studies have reported reduced natural and vaccine-derived protection against rotavirus gastroenteritis (RVGE) in low- and middle-income countries. While susceptibility of children to rotavirus is known to vary within and between settings, implications for estimation of immune protection are not well understood. We sought to re-estimate naturally-acquired protection against rotavirus infection and RVGE, and to understand how differences in susceptibility among children impacted estimates. We re-analyzed data from studies conducted in Mexico City, Mexico and Vellore, India. Cumulatively, 573 rotavirus-unvaccinated children experienced 1418 rotavirus infections and 371 episodes of RVGE over 17,636 child-months. We developed a model that characterized susceptibility to rotavirus infection and RVGE among children, accounting for aspects of the natural history of rotavirus and differences in transmission rates between settings. We tested whether model-generated susceptibility measurements were associated with demographic and anthropometric factors, and with the severity of RVGE symptoms. We identified greater variation in susceptibility to rotavirus infection and RVGE in Vellore than in Mexico City. In both cohorts, susceptibility to rotavirus infection and RVGE were associated with male sex, lower birth weight, lower maternal education, and having fewer siblings; within Vellore, susceptibility was also associated with lower socioeconomic status. Children who were more susceptible to rotavirus also experienced higher rates of rotavirus-negative diarrhea, and higher risk of moderate-to-severe symptoms when experiencing RVGE. Simulations suggested that discrepant estimates of naturally-acquired immunity against RVGE can be attributed, in part, to between-setting differences in susceptibility of children, but result primarily from the interaction of transmission rates with age-dependent risk for infections to cause RVGE. We found that more children in Vellore than in Mexico City belong to a high-risk group for rotavirus infection and RVGE, and demonstrate that unmeasured individual- and age-dependent susceptibility may influence estimates of naturally-acquired immune protection against RVGE.

Infrequent Transmission of Monovalent Human Rotavirus Vaccine Virus to Household Contacts of Vaccinated Infants in Malawi.

Horizontal transmission of rotavirus vaccine virus may contribute to indirect effects of rotavirus vaccine, but data are lacking from low-income countries. Serial stool samples were obtained from Malawian infants who received 2 doses of monovalent human rotavirus vaccine (RV1) (days 4, 6, 8, and 10 after vaccination) and from their household contacts (8-10 days after vaccine). RV1 vaccine virus in stool was detected using semiquantitative real-time reverse-transcription polymerase chain reaction. RV1 fecal shedding was detected in 41 of 60 vaccinated infants (68%) and in 2 of 147 household contacts (1.4%). Horizontal transmission of vaccine virus within households is unlikely to make a major contribution to RV1 indirect effects in Malawi.

Etiology of Diarrhea Among Hospitalized Children in Blantyre, Malawi, Following Rotavirus Vaccine Introduction: A Case-Control Study.

Despite rotavirus vaccination, diarrhea remains a leading cause of child mortality. We collected stool specimens from 684 children <5 years of age hospitalized with diarrhea (cases) and 527 asymptomatic community controls for 4 years after rotavirus vaccine introduction in Malawi. Specimens were tested for 29 pathogens, using polymerase chain reaction analysis. Three or more pathogens were detected in 71% of cases and 48% of controls. Pathogens significantly associated with diarrhea included rotavirus (in 34.7% of cases and 1.5% of controls), enteric adenovirus (in 29.1% and 2.7%, respectively), Cryptosporidium (in 27.8% and 8.2%, respectively), heat-stable enterotoxin-producing Escherichia coli (in 21.2% and 8.5%, respectively), typical enteropathogenic E. coli (in 18.0% and 8.3%, respectively), and Shigella/enteroinvasive E. coli (in 15.8% and 5.7%, respectively). Additional interventions are required to prevent diarrhea due to rotavirus and other common causal pathogens.

Forecasting Demand for the Typhoid Conjugate Vaccine in Low- and Middle-income Countries.

BACKGROUND: The World Health Organization (WHO) released a position paper in March 2018 calling for integration of a novel typhoid conjugate vaccine (TCV) into routine immunization along with catch-up campaigns for children up to age 15. Gavi, the Vaccine Alliance, has committed funding to help resource-constrained countries introduce this vaccine. In this article, the Typhoid Vaccine Acceleration Consortium forecasts demand if WHO recommendations are followed. METHODS: We built a model of global TCV introductions between 2020 and 2040 to estimate the demand of the vaccine for 133 countries. We estimated each country's year of introduction by examining its estimated incidence of typhoid fever, its history of introducing new vaccines, and any knowledge we have of its engagement with typhoid prevention, including intention to apply for Gavi funding. Our model predicted use in routine infant vaccination as well as campaigns targeting varying proportions of the unvaccinated population up to 15 years of age. RESULTS: Between 2020 and 2025, demand will predominantly come from African countries, many receiving Gavi support. After that, Asian countries generate most demand until 2030, when campaigns are estimated to end. Demand will then track the birth cohort of participating countries, suggesting an annual routine demand between 90 and 100 million doses. Peak demand is likely to occur between 2023 and 2026, approaching 300 million annual doses if campaign implementation is high. CONCLUSIONS: In our analysis, target population for catch-up campaigns is the main driver of uncertainty. At peak demand, there is some risk of exceeding presently estimated peak production capacity. Therefore, it will be important to carefully coordinate introductions, especially when accompanied by campaigns targeting large proportions of the eligible population.

Nonsecretor Histo-blood Group Antigen Phenotype Is Associated With Reduced Risk of Clinical Rotavirus Vaccine Failure in Malawian Infants.

BACKGROUND: Histo-blood group antigen (HBGA) Lewis/secretor phenotypes predict genotype-specific susceptibility to rotavirus gastroenteritis (RVGE). We tested the hypothesis that nonsecretor/Lewis-negative phenotype leads to reduced vaccine take and lower clinical protection following vaccination with G1P[8] rotavirus vaccine (RV1) in Malawian infants. METHODS: A cohort study recruited infants receiving RV1 at age 6 and 10 weeks. HBGA phenotype was determined by salivary enzyme-linked immunosorbent assay (ELISA). RV1 vaccine virus shedding was detected by quantitative real-time polymerase chain reaction (qRT-PCR) in stool collected on alternate days for 10 days post-immunization. Plasma rotavirus-specific immunoglobulin A was determined by ELISA pre- and post-immunization. In a case-control study, HBGA phenotype distribution was compared between RV1-vaccinated infants with RVGE and 1:1 age-matched community controls. Rotavirus genotype was determined by RT-PCR. RESULTS: In 202 cohort participants, neither overall vaccine virus fecal shedding nor seroconversion differed by HBGA phenotype. In 238 case-control infants, nonsecretor phenotype was less common in infants with clinical vaccine failure (odds ratio [OR], 0.39; 95% confidence interval [CI], 0.20-0.75). Nonsecretor phenotype was less common in infants with P[8] RVGE (OR, 0.12; 95% CI, 0.03-0.50) and P[4] RVGE (OR, 0.17; 95% CI, 0.04-0.75). Lewis-negative phenotype was more common in infants with P[6] RVGE (OR, 3.2; 95% CI, 1.4-7.2). CONCLUSIONS: Nonsecretor phenotype was associated with reduced risk of rotavirus vaccine failure. There was no significant association between HBGA phenotype and vaccine take. These data refute the hypothesis that high prevalence of nonsecretor/Lewis-negative phenotypes contributes to lower rotavirus vaccine effectiveness in Malawi.

Vaccine Effectiveness against DS-1-Like Rotavirus Strains in Infants with Acute Gastroenteritis, Malawi, 2013-2015.

Atypical DS-1-like G1P[8] rotaviruses emerged in 2013 in Malawi after rotavirus vaccine introduction. Vaccine effectiveness among infants hospitalized with acute DS-1-like G1P[8] rotavirus gastroenteritis was 85.6% (95% CI 34.4%-96.8%). These findings suggest that vaccine provides protection against these strains despite their emergence coinciding with vaccine introduction.

Emergence of Double- and Triple-Gene Reassortant G1P[8] Rotaviruses Possessing a DS-1-Like Backbone after Rotavirus Vaccine Introduction in Malawi.

To combat the high burden of rotavirus gastroenteritis, multiple African countries have introduced rotavirus vaccines into their childhood immunization programs. Malawi incorporated a G1P[8] rotavirus vaccine (Rotarix) into its immunization schedule in 2012. Utilizing a surveillance platform of hospitalized rotavirus gastroenteritis cases, we examined the phylodynamics of G1P[8] rotavirus strains that circulated in Malawi before (1998 to 2012) and after (2013 to 2014) vaccine introduction. Analysis of whole genomes obtained through next-generation sequencing revealed that all randomly selected prevaccine G1P[8] strains sequenced (n = 32) possessed a Wa-like genetic constellation, whereas postvaccine G1P[8] strains (n = 18) had a DS-1-like constellation. Phylodynamic analyses indicated that postvaccine G1P[8] strains emerged through reassortment events between human Wa- and DS-1-like rotaviruses that circulated in Malawi from the 1990s and hence were classified as atypical DS-1-like reassortants. The time to the most recent common ancestor for G1P[8] strains was from 1981 to 1994; their evolutionary rates ranged from 9.7 × 10-4 to 4.1 × 10-3 nucleotide substitutions/site/year. Three distinct G1P[8] lineages chronologically replaced each other between 1998 and 2014. Genetic drift was the likely driver for lineage turnover in 2005, whereas replacement in 2013 was due to reassortment. Amino acid substitution within the outer glycoprotein VP7 of G1P[8] strains had no impact on the structural conformation of the antigenic regions, suggesting that it is unlikely that they would affect recognition by vaccine-induced neutralizing antibodies. While the emergence of DS-1-like G1P[8] rotavirus reassortants in Malawi was therefore likely due to natural genotype variation, vaccine effectiveness against such strains needs careful evaluation.IMPORTANCE The error-prone RNA-dependent RNA polymerase and the segmented RNA genome predispose rotaviruses to genetic mutation and genome reassortment, respectively. These evolutionary mechanisms generate novel strains and have the potential to lead to the emergence of vaccine escape mutants. While multiple African countries have introduced a rotavirus vaccine, there are few data describing the evolution of rotaviruses that circulated before and after vaccine introduction. We report the emergence of atypical DS-1-like G1P[8] strains during the postvaccine era in Malawi. Three distinct G1P[8] lineages circulated chronologically from 1998 to 2014; mutation and reassortment drove lineage turnover in 2005 and 2013, respectively. Amino acid substitutions within the outer capsid VP7 glycoprotein did not affect the structural conformation of mapped antigenic sites, suggesting a limited effect on the recognition of G1-specific vaccine-derived antibodies. The genes that constitute the remaining genetic backbone may play important roles in immune evasion, and vaccine effectiveness against such atypical strains needs careful evaluation.