Estimating the incidence of rotavirus infection in children from India and Malawi from serial anti-rotavirus IgA titres.

Accurate estimates of rotavirus incidence in infants are crucial given disparities in rotavirus vaccine effectiveness from low-income settings. Sero-surveys are a pragmatic means of estimating incidence however serological data is prone to misclassification. This study used mixture models to estimate incidence of rotavirus infection from anti-rotavirus immunoglobulin A (IgA) titres in infants from Vellore, India, and Karonga, Malawi. IgA titres were measured using serum samples collected at 6 month intervals for 36 months from 373 infants from Vellore and 12 months from 66 infants from Karonga. Mixture models (two component Gaussian mixture distributions) were fit to the difference in titres between time points to estimate risk of sero-positivity and derive incidence estimates. A peak incidence of 1.05(95% confidence interval [CI]: 0.64, 1.64) infections per child-year was observed in the first 6 months of life in Vellore. This declined incrementally with each subsequent time interval. Contrastingly in Karonga incidence was greatest in the second 6 months of life (1.41 infections per child year [95% CI: 0.79, 2.29]). This study demonstrates that infants from Vellore experience peak rotavirus incidence earlier than those from Karonga. Identifying such differences in transmission patterns is important in informing vaccine strategy, particularly where vaccine effectiveness is modest

Estimating the incidence of rotavirus infection in children from India and Malawi from serial anti-rotavirus IgA titres.

Accurate estimates of rotavirus incidence in infants are crucial given disparities in rotavirus vaccine effectiveness from low-income settings. Sero-surveys are a pragmatic means of estimating incidence however serological data is prone to misclassification. This study used mixture models to estimate incidence of rotavirus infection from anti-rotavirus immunoglobulin A (IgA) titres in infants from Vellore, India, and Karonga, Malawi. IgA titres were measured using serum samples collected at 6 month intervals for 36 months from 373 infants from Vellore and 12 months from 66 infants from Karonga. Mixture models (two component Gaussian mixture distributions) were fit to the difference in titres between time points to estimate risk of sero-positivity and derive incidence estimates. A peak incidence of 1.05(95% confidence interval [CI]: 0.64, 1.64) infections per child-year was observed in the first 6 months of life in Vellore. This declined incrementally with each subsequent time interval. Contrastingly in Karonga incidence was greatest in the second 6 months of life (1.41 infections per child year [95% CI: 0.79, 2.29]). This study demonstrates that infants from Vellore experience peak rotavirus incidence earlier than those from Karonga. Identifying such differences in transmission patterns is important in informing vaccine strategy, particularly where vaccine effectiveness is modest

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

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

BackgroundRotavirus 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.MethodsIn 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 ResultsIn 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.ConclusionsIn 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

Population Impact and Effectiveness of Monovalent Rotavirus Vaccination in Urban Malawian Children 3 Years After Vaccine Introduction: Ecological and Case-Control Analyses.

BACKGROUND: Rotavirus vaccines have been introduced in many low-income African countries including Malawi in 2012. Despite early evidence of vaccine impact, determining persistence of protection beyond infancy, the utility of the vaccine against specific rotavirus genotypes, and effectiveness in vulnerable subgroups is important. METHODS: We compared rotavirus prevalence in diarrheal stool and hospitalization incidence before and following rotavirus vaccine introduction in Malawi. Using case-control analysis, we derived vaccine effectiveness (VE) in the second year of life and for human immunodeficiency virus (HIV)-exposed and stunted children. RESULTS: Rotavirus prevalence declined concurrent with increasing vaccine coverage, and in 2015 was 24% compared with prevaccine mean baseline in 1997-2011 of 32%. Since vaccine introduction, population rotavirus hospitalization incidence declined in infants by 54.2% (95% confidence interval [CI], 32.8-68.8), but did not fall in older children. Comparing 241 rotavirus cases with 692 test-negative controls, VE was 70.6% (95% CI, 33.6%-87.0%) and 31.7% (95% CI, -140.6% to 80.6%) in the first and second year of life, respectively, whereas mean age of rotavirus cases increased from 9.3 to 11.8 months. Despite higher VE against G1P[8] than against other genotypes, no resurgence of nonvaccine genotypes has occurred. VE did not differ significantly by nutritional status (78.1% [95% CI, 5.6%-94.9%] in 257 well-nourished and 27.8% [95% CI, -99.5% to 73.9%] in 205 stunted children;P= .12), or by HIV exposure (60.5% [95% CI, 13.3%-82.0%] in 745 HIV-unexposed and 42.2% [95% CI, -106.9% to 83.8%] in 174 exposed children;P= .91). CONCLUSIONS: Rotavirus vaccination in Malawi has resulted in reductions in disease burden in infants <12 months, but not in older children. Despite differences in genotype-specific VE, no genotype has emerged to suggest vaccine escape. VE was not demonstrably affected by HIV exposure or stunting

Rapid emergence of multidrug resistant, H58-lineage Salmonella typhi in Blantyre, Malawi.

INTRODUCTION: Between 1998 and 2010, S. Typhi was an uncommon cause of bloodstream infection (BSI) in Blantyre, Malawi and it was usually susceptible to first-line antimicrobial therapy. In 2011 an increase in a multidrug resistant (MDR) strain was detected through routine bacteriological surveillance conducted at Queen Elizabeth Central Hospital (QECH). METHODS: Longitudinal trends in culture-confirmed Typhoid admissions at QECH were described between 1998-2014. A retrospective review of patient cases notes was conducted, focusing on clinical presentation, prevalence of HIV and case-fatality. Isolates of S. Typhi were sequenced and the phylogeny of Typhoid in Blantyre was reconstructed and placed in a global context. RESULTS: Between 1998-2010, there were a mean of 14 microbiological diagnoses of Typhoid/year at QECH, of which 6.8% were MDR. This increased to 67 in 2011 and 782 in 2014 at which time 97% were MDR. The disease predominantly affected children and young adults (median age 11 [IQR 6-21] in 2014). The prevalence of HIV in adult patients was 16.7% [8/48], similar to that of the general population (17.8%). Overall, the case fatality rate was 2.5% (3/94). Complications included anaemia, myocarditis, pneumonia and intestinal perforation. 112 isolates were sequenced and the phylogeny demonstrated the introduction and clonal expansion of the H58 lineage of S. Typhi. CONCLUSIONS: Since 2011, there has been a rapid increase in the incidence of multidrug resistant, H58-lineage Typhoid in Blantyre. This is one of a number of reports of the re-emergence of Typhoid in Southern and Eastern Africa. There is an urgent need to understand the reservoirs and transmission of disease and how to arrest this regional increase

Population impact and effectiveness of monovalent rotavirus vaccination in urban Malawian children 3 years after vaccine introduction: ecological and case-control analyses

Background. Rotavirus vaccines have been introduced in many low-income African countries including Malawi in 2012. Despite early evidence of vaccine impact, determining persistence of protection beyond infancy, the utility of the vaccine against specific rotavirus genotypes, and effectiveness in vulnerable subgroups is important. Methods. We compared rotavirus prevalence in diarrheal stool and hospitalization incidence before and following rotavirus vaccine introduction in Malawi. Using case-control analysis, we derived vaccine effectiveness (VE) in the second year of life and for human immunodeficiency virus (HIV)–exposed and stunted children. Results. Rotavirus prevalence declined concurrent with increasing vaccine coverage, and in 2015 was 24% compared with prevaccine mean baseline in 1997–2011 of 32%. Since vaccine introduction, population rotavirus hospitalization incidence declined in infants by 54.2% (95% confidence interval [CI], 32.8–68.8), but did not fall in older children. Comparing 241 rotavirus cases with 692 test-negative controls, VE was 70.6% (95% CI, 33.6%–87.0%) and 31.7% (95% CI, −140.6% to 80.6%) in the first and second year of life, respectively, whereas mean age of rotavirus cases increased from 9.3 to 11.8 months. Despite higher VE against G1P[8] than against other genotypes, no resurgence of nonvaccine genotypes has occurred. VE did not differ significantly by nutritional status (78.1% [95% CI, 5.6%–94.9%] in 257 well-nourished and 27.8% [95% CI, −99.5% to 73.9%] in 205 stunted children; P = .12), or by HIV exposure (60.5% [95% CI, 13.3%–82.0%] in 745 HIV-unexposed and 42.2% [95% CI, −106.9% to 83.8%] in 174 exposed children; P = .91). Conclusions. Rotavirus vaccination in Malawi has resulted in reductions in disease burden in infants &lt;12 months, but not in older children. Despite differences in genotype-specific VE, no genotype has emerged to suggest vaccine escape. VE was not demonstrably affected by HIV exposure or stunting

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

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