Kristen D.C. Lewis

Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in Asia: a randomised, double-blind, placebo-controlled trial

BACKGROUND Rotavirus vaccine has proved effective for prevention of severe rotavirus gastroenteritis in infants in developed countries, but no efficacy studies have been done in developing countries in Asia. We assessed the clinical efficacy of live oral pentavalent rotavirus vaccine for prevention of severe rotavirus gastroenteritis in infants in Bangladesh and Vietnam. METHODS In this multicentre, double-blind, placebo-controlled trial, undertaken in rural Matlab, Bangladesh, and urban and periurban Nha Trang, Vietnam, infants aged 4-12 weeks without symptoms of gastrointestinal disorders were randomly assigned (1:1) to receive three oral doses of pentavalent rotavirus vaccine 2 mL or placebo at around 6 weeks, 10 weeks, and 14 weeks of age, in conjunction with routine infant vaccines including oral poliovirus vaccine. Randomisation was done by computer-generated randomisation sequence in blocks of six. Episodes of gastroenteritis in infants who presented to study medical facilities were reported by clinical staff and from parent recollection. The primary endpoint was severe rotavirus gastroenteritis (Vesikari score >or=11) arising 14 days or more after the third dose of placebo or vaccine to end of study (March 31, 2009; around 21 months of age). Analysis was per protocol; infants who received scheduled doses of vaccine or placebo without intervening laboratory-confirmed naturally occurring rotavirus disease earlier than 14 days after the third dose and had complete clinical and laboratory results were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT00362648. FINDINGS 2036 infants were randomly assigned to receive pentavalent rotavirus vaccine (n=1018) or placebo (n=1018). 991 infants assigned to pentavalent rotavirus vaccine and 978 assigned to placebo were included in the per-protocol analysis. Median follow up from 14 days after the third dose of placebo or vaccine until final disposition was 498 days (IQR 480-575). 38 cases of severe rotavirus gastroenteritis (Vesikari score >or=11) were reported during more than 1197 person-years of follow up in the vaccine group, compared with 71 cases in more than 1156 person years in the placebo group, resulting in a vaccine efficacy of 48.3% (95% CI 22.3-66.1) against severe disease (p=0.0005 for efficacy >0%) during nearly 2 years of follow-up. 25 (2.5%) of 1017 infants assigned to receive vaccine and 20 (2.0%) of 1018 assigned to receive placebo had a serious adverse event within 14 days of any dose. The most frequent serious adverse event was pneumonia (vaccine 12 [1.2%]; placebo 15 [1.5%]). INTERPRETATION In infants in developing countries in Asia, pentavalent rotavirus vaccine is safe and efficacious against severe rotavirus gastroenteritis, and our results support expanded WHO recommendations to promote its global use. FUNDING PATH (GAVI Alliance grant) and Merck.

A live attenuated H5N1 vaccine induces long-term immunity in the absence of a primary antibody response

BACKGROUND Highly pathogenic avian influenza A(H5N1) causes severe infections in humans. We generated 2 influenza A(H5N1) live attenuated influenza vaccines for pandemic use (pLAIVs), but they failed to elicit a primary immune response. Our objective was to determine whether the vaccines primed or established long-lasting immunity that could be detected by administration of inactivated subvirion influenza A(H5N1) vaccine (ISIV). METHODS The following groups were invited to participate in the study: persons who previously received influenza A(H5N1) pLAIV; persons who previously received an irrelevant influenza A(H7N3) pLAIV; and community members who were naive to influenza A(H5N1) and LAIV. LAIV-experienced subjects received a single 45-μg dose of influenza A(H5N1) ISIV. Influenza A(H5N1)- and LAIV-naive subjects received either 1 or 2 doses of ISIV. RESULTS In subjects who had previously received antigenically matched influenza A(H5N1) pLAIV followed by 1 dose of ISIV compared with those who were naive to influenza A(H5N1) and LAIV and received 2 doses of ISIV, we observed an increased frequency of antibody response (82% vs 50%, by the hemagglutination inhibition assay) and a significantly higher antibody titer (112 vs 76; P = .04). The affinity of antibody and breadth of cross-clade neutralization was also enhanced in influenza A(H5N1) pLAIV-primed subjects. CONCLUSIONS ISIV administration unmasked long-lasting immunity in influenza A(H5N1) pLAIV recipients, with a rapid, high-titer, high-quality antibody response that was broadly cross-reactive across several influenza A(H5N1) clades. CLINICAL TRIALS REGISTRATION NCT01109329.

Projected health and economic impact of rotavirus vaccination in GAVI-eligible countries: 2011–2030

Rotavirus is the leading cause of diarrheal disease in children under 5 years of age. It is responsible for more than 450,000 deaths each year, with more than 90% of these deaths occurring in low-resource countries eligible for support by the GAVI Alliance. Significant efforts made by the Alliance and its partners are providing countries with the opportunity to introduce rotavirus vaccines into their national immunization programs, to help prevent childhood illness and death. We projected the cost-effectiveness and health impact of rotavirus vaccines in GAVI-eligible countries, to assist decision makers in prioritizing resources to achieve the greatest health benefits for their populations. A decision-analytic model was used to project the health outcomes and direct costs of a birth cohort in the target population, with and without a rotavirus vaccine. Current data on disease burden, vaccine efficacy, immunization rates, and costs were used in the model. Vaccination in GAVI-eligible countries would prevent 2.46 million childhood deaths and 83 million disability-adjusted life years (DALYs) from 2011 to 2030, with annual reductions of 180,000 childhood deaths at peak vaccine uptake. The cost per DALY averted is

A live attenuated influenza A(H5N1) vaccine induces long-term immunity in the absence of a primary antibody response.

42 for all GAVI countries combined, over the entire period. Rotavirus vaccination would be considered very cost-effective for the entire cohort of GAVI countries, and in each country individually, as cost-effectiveness ratios are less than the gross domestic product (GDP) per capita. Vaccination is most cost-effective and has the greatest impact in regions with high rotavirus mortality. Rotavirus vaccination in GAVI-eligible countries is very cost-effective and is projected to substantially reduce childhood mortality in this population.

Rotavirus vaccines: Update on global impact and future priorities

BACKGROUND Highly pathogenic avian influenza A(H5N1) causes severe infections in humans. We generated 2 influenza A(H5N1) live attenuated influenza vaccines for pandemic use (pLAIVs), but they failed to elicit a primary immune response. Our objective was to determine whether the vaccines primed or established long-lasting immunity that could be detected by administration of inactivated subvirion influenza A(H5N1) vaccine (ISIV). METHODS The following groups were invited to participate in the study: persons who previously received influenza A(H5N1) pLAIV; persons who previously received an irrelevant influenza A(H7N3) pLAIV; and community members who were naive to influenza A(H5N1) and LAIV. LAIV-experienced subjects received a single 45-μg dose of influenza A(H5N1) ISIV. Influenza A(H5N1)- and LAIV-naive subjects received either 1 or 2 doses of ISIV. RESULTS In subjects who had previously received antigenically matched influenza A(H5N1) pLAIV followed by 1 dose of ISIV compared with those who were naive to influenza A(H5N1) and LAIV and received 2 doses of ISIV, we observed an increased frequency of antibody response (82% vs 50%, by the hemagglutination inhibition assay) and a significantly higher antibody titer (112 vs 76; P = .04). The affinity of antibody and breadth of cross-clade neutralization was also enhanced in influenza A(H5N1) pLAIV-primed subjects. CONCLUSIONS ISIV administration unmasked long-lasting immunity in influenza A(H5N1) pLAIV recipients, with a rapid, high-titer, high-quality antibody response that was broadly cross-reactive across several influenza A(H5N1) clades. CLINICAL TRIALS REGISTRATION NCT01109329.

Efficacy of the oral pentavalent rotavirus vaccine in Mali

Early rotavirus vaccine adopter countries in the Americas, Europe, and in Australia have documented substantial declines in rotavirus disease burden following the introduction of vaccination. However, the full public health impact of rotavirus vaccines has not been realized as they have not been introduced into routine immunization programs in countries of Africa and Asia with the highest rotavirus disease morbidity and mortality burden. In this article, we review the epidemiology of rotavirus disease, the development and current status of rotavirus vaccines including newly available vaccine impact data from early-introducer countries, and future priorities for implementation and monitoring of rotavirus vaccination programs in developing countries.

A systematic review of rotavirus strain diversity in India, Bangladesh, and Pakistan

The oral, pentavalent rotavirus vaccine (PRV), RotaTeq was assessed for prevention of severe rotavirus gastroenteritis (RVGE) in young children in two multi-site, randomized, placebo-controlled field trials; one in Asia (Vietnam and Bangladesh) and the other in sub-Saharan Africa (Ghana, Kenya and Mali). The efficacy results for the Mali site of the multi-country trial are presented here. We randomly assigned infants in a 1:1 ratio to receive 3 doses of PRV/placebo at approximately 6, 10, and 14 weeks of age. Gastroenteritis episodes were captured passively at the local health centers and by home visits. The primary study outcome was severe RVGE, as defined by a score of ≥ 11 using the Vesikari Clinical Scoring System occurring ≥ 14 days after the third dose until the end of the study. Other efficacy analyses included efficacy against severe RVGE through the first year and during the second years of life, as well as efficacy after receiving at least one dose of vaccine. In total, 1960 infants were enrolled in the trial at the Mali site and sera were collected on a subset of infants (approximately 150) for immunogenicity testing. In the first year of follow-up, largely due to cultural practices to visit traditional healers as the first point of care, the point estimate of efficacy was unreliable: the per protocol vaccine efficacy against severe RVGE was 1% (95% confidence interval [CI]: -431.7, 81.6); the intention-to-treat vaccine efficacy was 42.9% (95% CI: -125.7, 87.7). During the second year of follow-up, after the surveillance system was modified to adapt to local customs and health care seeking practices, the point estimate of per-protocol vaccine efficacy was 19.2% (95% CI: -23.1,47.3%). 82.5% of Malian infants (95% CI: 70.1,91.3%) who received PRV mounted a seroresponse (≥ 3-fold rise from baseline (prevaccination) to post-dose 3 vaccination) of anti-rotavirus immunoglobulin A antibody, with a post third-dose geometric mean titer (GMT) of 31.3 units/mL. By contrast, only 20.0% of placebo recipients (95% CI: 10.0, 33.7%) developed a seroresponse and the post-third dose GMT was 3.2 units/mL. None of the serious clinical adverse events observed were considered to be vaccine-related.

Use of an expanded gold standard to estimate the accuracy of colposcopy and visual inspection with acetic acid

Of the estimated half-million deaths from rotavirus globally each year, approximately one-third (N = 160,000 deaths) occur in the Indian subcontinent (defined as India, Bangladesh, and Pakistan). Two commercial vaccines are available for use and recommended by WHO, although the prohibitive vaccine price has limited their introduction into routine childhood immunization programs. New rotavirus vaccines are in late clinical development, including two advanced candidates in India. As significant shifts in rotavirus strain diversity have occurred in the past three decades and questions remain regarding whether strain replacement may occur following introduction of rotavirus vaccines, it is important to understand the temporal and regional strain diversity profile before vaccine introduction. We reviewed 33 peer-reviewed manuscripts from the Indian subcontinent and found that the most common G-types (G1-4) and P-types (P[4] and P[8]) globally accounted for three-fourths of all strains in the subcontinent. However, strains varied by region, and temporal analysis showed the decline of G3 and G4 in recent years and the emergence of G9 and G12. Our findings underscore the large diversity of rotavirus strains in the Indian subcontinent and highlight the need to conduct surveillance on a regional scale to better understand strain diversity before and after rotavirus vaccine introduction.

Efficacy of a Russian-backbone live attenuated influenza vaccine among young children in Bangladesh: a randomised, double-blind, placebo-controlled trial

We estimate the accuracy of colposcopy and visual inspection with acetic acid (VIA) while minimizing the effects of misclassification bias, and maximizing ascertainment of disease. VIA was performed by experienced physicians on a population‐based sample of women aged 30 to 49 years in rural Shanxi province, China. Each woman received VIA, liquid‐based cytology (LBC) and hybrid capture 2 (hc2, QIAGEN, Gaithersburg, MD; formerly Digene Corporation). Any woman who tested positive on any test had colposcopy, endocervical curettage (ECC) with directed biopsies as necessary and 4‐quadrant random biopsies from normal‐appearing areas of the cervix. A standard diagnosis based on colposcopy and directed biopsy, and an expanded diagnosis including ECC and 4‐quadrant random biopsy were generated for each woman. In 1,839 women, use of the expanded versus the standard diagnostic criteria increased the prevalence of histologically confirmed high‐grade cervical intraepithelial neoplasia and cancer (CIN2+) from 3.2% (59/1,839) to 4.2% (77/1,839) and decreased the sensitivity of VIA for CIN2+ from 69.5% (95% CI: 56.8–79.8) to 58.4% (95% CI: 47.3–68.8%) with little change in specificity of approximately 89%. Compared with the expanded diagnostic criterion, the sensitivity of a visual diagnosis of high‐grade CIN or cancer by a colposcopist was 49.4% (95% CI: 38.2–60.5). The use of an expanded diagnostic criterion in this study yielded more conservative estimates of the sensitivity of VIA and colposcopy.

A Randomized, Controlled Trial of the Impact of Alternative Dosing Schedules on the Immune Response to Human Rotavirus Vaccine in Rural Ghanaian Infants

Summary Background The rates of influenza illness and associated complications are high among children in Bangladesh. We assessed the clinical efficacy and safety of a Russian-backbone live attenuated influenza vaccine (LAIV) at two field sites in Bangladesh. Methods Between Feb 27 and April 9, 2013, children aged 2–4 years in urban Kamalapur and rural Matlab, Bangladesh, were randomly assigned in a 2:1 ratio, according to a computer-generated schedule, to receive one intranasal dose of LAIV or placebo. After vaccination, we monitored children in weekly home visits until Dec 31, 2013, with study clinic surveillance for influenza illness. The primary outcome was symptomatic, laboratory-confirmed influenza illness due to vaccine-matched strains. Analysis was per protocol. The trial is registered with ClinicalTrials.gov, number NCT01797029. Findings Of 1761 children enrolled, 1174 received LAIV and 587 received placebo. Laboratory-confirmed influenza illness due to vaccine-matched strains was seen in 93 (15·8%) children in the placebo group and 79 (6·7%) in the LAIV group. Vaccine efficacy of LAIV for vaccine-matched strains was 57·5% (95% CI 43·6–68·0). The vaccine was well tolerated, and adverse events were balanced between the groups. The most frequent adverse events were tachypnoea (n=86 in the LAIV group and n=54 in the placebo group), cough (n=73 and n=43), and runny nose (n=68 and n=39), most of which were mild. Interpretation This single-dose Russian-backbone LAIV was safe and efficacious at preventing symptomatic laboratory-confirmed influenza illness due to vaccine-matched strains. LAIV programmes might reduce the burden of influenza illness in Bangladesh. Funding The Bill & Melinda Gates Foundation.