Estimated public health impact of human rotavirus vaccine (HRV) and pneumococcal polysaccharide protein D-conjugate vaccine (PHiD-CV) on child morbidity and mortality in Gavi-supported countries.

Vaccine impact models against rotavirus disease (RD) and pneumococcal disease (PD) in low- and middle-income countries assume vaccine coverage based on other vaccines. We propose to assess the impact on severe disease cases and deaths avoided based on vaccine doses delivered by one manufacturer to Gavi-supported countries. From the number of human rotavirus vaccine (HRV) and pneumococcal polysaccharide protein D-conjugate vaccine (PHiD-CV) doses delivered, we estimated the averted burden of disease 1) in a specific year and 2) for all children vaccinated during the study period followed-up until 5 years (y) of age. Uncertainty of the estimated impact was assessed in a probabilistic sensitivity analysis using Monte-Carlo simulations to provide 95% confidence intervals. From 2009 to 2019, approximately 143 million children received HRV in 57 Gavi-supported countries, avoiding an estimated 18.7 million severe RD cases and 153,000, deaths. From 2011 to 2019, approximately 146 million children received PHiD-CV in 36 countries, avoiding an estimated 5.0 million severe PD cases and 587,000 deaths. The number of severe cases and deaths averted for all children vaccinated during the study period until 5 years of age were about 23.2 million and 190,000, respectively, for HRV, and 6.6 million and 749,000, respectively, for PHiD-CV. Models based on doses delivered help to assess the impact of vaccination, plan vaccination programs and understand public health benefits. In 2019, HRV and PHiD-CV doses delivered over a 5-y period may have, on average, averted nine severe disease cases every minute and one child death every 4 min.

What is the context?The WHO added the pneumococcal conjugate vaccine and the rotavirus vaccine in the recommended vaccination schedule of all countries in 2007 and 2009, respectively.Previous studies estimated the public health benefit of these vaccines by approximating the number of children who received them.What is new?We used an alternative approach to estimate the benefit based on actual number of doses of the vaccines, human rotavirus vaccine (HRV; Rotarix) and pneumococcal polysaccharide protein D-conjugate vaccine (PHiD-CV; Synflorix) delivered to each country considered.The study analyzed data from children under 5 years of age in 60 Gavi-supported countries by identifying the number of vaccine doses delivered, estimating the number of children fully covered, applying the country-specific disease epidemiology, estimating the number of severe disease cases and deaths avoided.From 2009 to 2019, approximately 143 million children were vaccinated with HRV avoiding an estimated 18.7 million severe rotavirus disease cases and 153,000 deaths.From 2011 to 2019, about 146 million children were vaccinated with pneumococcal vaccine avoiding an estimated 5.0 million severe pneumococcal disease cases and 587,000 deaths.What is the impact? The benefit of HRV and PHiD-CV in Gavi-supported countries is often estimated based on assumptions of vaccine coverage rates.A modeling approach based on doses delivered by the vaccine manufacturer can provide an additional view on the potential vaccine benefits and improve planning, contribution, and sustainability of the immunization programs at a country level.In 2019, HRV and PHiD-CV together averted nine cases of severe disease each minute and one child death every 4 minutes.

Established and new rotavirus vaccines: a comprehensive review for healthcare professionals.

Robust scientific evidence related to two rotavirus (RV) vaccines available worldwide demonstrates their significant impact on RV disease burden. Improving RV vaccination coverage may result in better RV disease control. To make RV vaccination accessible to all eligible children worldwide and improve vaccine effectiveness in high-mortality settings, research into new RV vaccines continues. Although current and in-development RV vaccines differ in vaccine design, their common goal is the reduction of RV disease risk in children <5 years old for whom disease burden is the most significant. Given the range of RV vaccines available, informed decision-making is essential regarding the choice of vaccine for immunization. This review aims to describe the landscape of current and new RV vaccines, providing context for the assessment of their similarities and differences. As data for new vaccines are limited, future investigations will be required to evaluate their performance/added value in a real-world setting.

PLAIN LANGUAGE SUMMARYThe diseaseRotaviruses are a leading cause of acute diarrhea, also called gastroenterities, among young children. They can lead to servere dehydration, hospitilization, and even death.Several vaccines against rotavirus disease have been developed. Their design is based on:weakened human rotavirus that mimic natural infection without causing disease, such as Rotarix, Rotavin-M1, Rotavac and RV3-BB (not yet marketed)non-infective animal viruses such as RotaTeq, Rotasiil or LLR.new concepts, such as inactivated vaccinesWhat is new?We reviewed the current, recently launched and soon-to-be-launched rotavirus vaccines and found that:Rotarix and RotaTeq have been used globally for more than a decade with demonstrated impact and favourable safety profileLimited data on the impact and safety profile are available to date for:Rotavin-M1 and LLR vaccines, locally marketed in Vietnam and China, respectivelyRotavac and Rotasiil, licensed in indiaNew vaccine concepts have been mainly investigated animal models with encouraging resultsWhat is the impact?Despite their different designs, the current rotavirus vaccines demonstrate effectiveness in protecting against rotairus gastroenterits.Data for most recent vacciness are currently limited, for which additional data are needed to demonstrate how they will perform on a larger scale, their added value in a real setting and ther safety profile.

Rotavirus vaccines performance: dynamic interdependence of host, pathogen and environment.

INTRODUCTION: As of January 2021, rotavirus vaccination programs have been implemented in 109 countries and their use has resulted in a positive impact on rotavirus-related diarrheal hospitalizations and mortality in children below 5 years of age. Despite these successes, several countries in Africa and Asia where disease burden is high have not yet implemented rotavirus vaccination at all or at a scale sufficient enough to demonstrate impact. This could be, among other reasons, due to poor vaccine coverage and the modest levels of efficacy and effectiveness of the vaccines in these resource-limited settings. AREAS COVERED: We review various factors related to the human host (malnutrition, maternally derived antibodies and breastfeeding, genetic factors, blood group, and co-administration with oral polio vaccine), rotavirus pathogen (force of infection, strain diversity and coinfections), and the environment (related to the human microbiome) which reflect complex and interconnected processes leading to diminished vaccine performance in resource-limited settings. EXPERT OPINION: Addressing the limiting factors for vaccine efficacy is needed but likely to take a long time to be resolved. An immediate solution is to increase the immunization coverage to higher values generating an overall effect of adequate proportion of protected population to reduce the prevalence of rotavirus disease.

PLAIN LANGUAGE SUMMARYWhat is the context?Rotavirus is contagious and causes severe diarrhea in children below 5 years of age. It caused 128,500 deaths and 258 million episodes of diarrhea in 2016.Vaccines protecting children from rotavirus are given orally and have been implemented in 109 countries and used for more than a decade. They considerably decreased the number of hospitalizations and deaths.Several Asian and African countries experience rotavirus infections in large numbers and lag behind in implementing rotavirus vaccination programs.In these countries, rotavirus vaccines only prevent a smaller percentage of severe cases. The reasons for this reduction in vaccination impact are not widely known.What is new?We reviewed the literature to identify the reasons that could explain the differences in vaccination impact worldwide.Factors that might influence the impact of vaccination include Infected children (malnutrition, breastfeeding, blood group, and co-administration with oral polio vaccine);Circulating virus(es) (force of infection, number of new strains, and coinfections with other pathogens) Environment: human microbiome (microorganisms at the surface and in the body; that could be altered by diet, method of childbirth, or hygiene).Why is this important?In summary, rotavirus vaccination has reduced rotavirus-associated hospitalizations and deaths; however, more research is needed to understand the factors influencing the impact of vaccination in order to optimize them. (see Figure 1 ­ Graphical PLS).

Rotavirus vaccination and intussusception: a paradigm shift?

Rotavirus (RV) is one of the leading causes of severe childhood gastroenteritis in children <5 years of age. Several countries have successfully implemented vaccination against RV disease; however, hesitancy to include RV vaccination in the national immunization program exists and relates, among other reasons, to the results of international post-licensure studies of RV vaccines that established an increased risk of intussusception (IS) in infants following immunization. IS is one of the major causes of bowel obstruction in infants between 4 and 10 months of age. Some studies have investigated the etiology of IS, including the role of natural RV infection and available evidence suggests that RV disease may be an independent risk factor for IS. In this regard, the benefit-risk profile of RV vaccination, which is recognized as positive, could potentially turn out to be even more favorable in preventing IS cases triggered by RV disease. However, further research is prompted to quantify the IS risk attributable to RV disease.

Lessons Learned from Long-Term Assessment of Rotavirus Vaccination in a High-Income Country: The Case of the Rotavirus Vaccine Belgium Impact Study (RotaBIS).

INTRODUCTION: The rotavirus (RV) vaccine Belgium Impact Study (RotaBIS) evaluated the vaccine effect on RV-related hospital care in children up to 5 years old over a period of 13 years. Different forces were identified that influence the reduction in hospital care. Our analysis aims to report on the current RotaBIS dataset and explore through model simulation whether, how, and when the results could have been improved. METHODS: As performed in previous assessments, this analysis evaluated RV-related events per year, per age group, RV nosocomial infections, hospitalization duration, and herd effect. It subsequently identified results that were surprising or unexpected. To know whether those data could have been improved through specific interventions, we developed a model with the forces acting on the disease transmission and the vaccine effect on RV-related hospital care. Scenario analysis of the forces should explain the current findings and identify ways to optimize the results. RESULTS: The RotaBIS data show that annual RV-related hospital cases (n = 1345 pre-vaccination) dropped by 70% (95% confidence interval [CI] 66-74%) by year 5 (n = 395) after vaccine introduction, and by 84% (95% CI 79-89%) by year 10 (n = 217). The herd effect during the first year was limited to 14% extra gain. During the last 5 years, small disease increases were seen biennially. The simulation model indicates that higher vaccine coverage of the major transmitters during the peak season of the first year of vaccination could have reduced RV-related hospital care by nearly 90% at 5 and 10 years after vaccine introduction owing to a higher herd effect. The smaller peaks observed in recent years would have been dramatically reduced. CONCLUSION: The current RotaBIS data show a maintained reduction, around 76%, in RV hospitalization cases. Simulations show that these results could have been improved to an important extent with a more optimal initiation of the vaccination program. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01563146 and NCT01563159.

Fifteen years of experience with the oral live-attenuated human rotavirus vaccine: reflections on lessons learned.

INTRODUCTION: Rotavirus (RV) disease remains a prominent cause of disease burden in children <5 years of age worldwide. However, implementation of RV vaccination has led to significant reductions in RV mortality, compared to the pre-vaccination era. This review presents 15 years of real-world experience with the oral live-attenuated human RV vaccine (HRV; Rotarix). HRV is currently introduced in ≥80 national immunization programs (NIPs), as 2 doses starting from 6 weeks of age. AREAS COVERED: The clinical development of HRV and post-marketing experience indicating the impact of HRV vaccination on RV disease was reviewed. EXPERT OPINION: In clinical trials, HRV displayed an acceptable safety profile and efficacy against RV-gastroenteritis, providing broad protection against heterotypic RV strains by reducing the consequences of severe RV disease in infants. Real-world evidence shows substantial, rapid reduction in the number of RV infections and associated hospitalizations following introduction of HRV in NIPs, regardless of economic setting. Indirect effects against RV disease are also observed, such as herd protection, decrease in nosocomial infections incidence, and a reduction of disease-related societal/healthcare costs. However, not all countries have implemented RV vaccination. Coverage remains suboptimal and should be improved to maximize the benefits of RV vaccination.

Dynamics of G2P[4] strain evolution and rotavirus vaccination: A review of evidence for Rotarix.

Rotavirus (RV) gastroenteritis is a vaccine-preventable disease that creates high medical and economic burden in both developed and developing countries. Worldwide, more than 100 countries have introduced RV vaccines in their national immunization programs, and the remarkable impact of reducing the burden of severe childhood gastroenteritis has been unequivocally demonstrated. Currently, 2 oral vaccines (Rotarix, GSK and RotaTeq, Merck) are widely utilized. Recent temporary increases in the relative prevalence of G2P[4] RV strains have been observed in countries implementing RV vaccination. This comprehensive literature review aims to provide an insight on RV genotype evolution in the context of mass vaccination with Rotarix, particularly in the case of G2P[4]. In the post-vaccine era, strain surveillance data indicated temporal and spatial changes in countries both with and without RV vaccination programs. Annual fluctuations in G2P[4] prevalence seem to occur naturally, with no substantial differences between countries using Rotarix, RotaTeq or mixed vaccination programs. Moreover, Rotarix has been shown to be efficacious and effective against gastroenteritis caused by non-vaccine strains, including G2P[4]. These data indicate that shifts in RV genotype distribution are likely to constitute an inherent process of virus evolution to infect the human gut. Following RV vaccine introduction, incidences of RV gastroenteritis declined dramatically and mass vaccination will likely maintain this status, despite possible fluctuations in the relative distribution of genotypes. There is no conclusive evidence of unusual burst of new or vaccine-escape strains since global RV vaccines use. The emergence of strains with a potential to increase the current burden of RV disease should be continuously monitored and can only be established by exhaustive characterization of strains, including whole genomic sequencing. Given the natural fluctuations in RV strains over time, caution is advised when interpreting temporal changes in RV strain dynamics, as they could mistakenly be attributed to vaccination.

Systematic literature review on the safety and immunogenicity of rotavirus vaccines when co-administered with meningococcal vaccines.

This study is aimed to review the published evidence on safety, immunogenicity, and efficacy of rotavirus vaccines when co-administered with meningococcal vaccines in infants. A systematic literature search was performed in four databases containing peer-reviewed articles and conference abstracts. In total, twelve articles were included in the review; 11 provided information on safety and five on the immunogenicity of rotavirus vaccines following co-administration. No paper was found on efficacy. Additional routine vaccines were administered in all studies. The safety analysis was mainly focused on fever, vomiting, diarrhea, intussusception, and changes in eating habits. Overall, safety profiles and immune responses associated with rotavirus vaccination were comparable between infants co-administered with rotavirus and meningococcal vaccines and infants receiving rotavirus vaccines without meningococcal vaccines. Although data are limited, co-administration of rotavirus and meningococcal vaccines does not appear to interfere with the safety or immunogenicity of rotavirus vaccines.

Letter to the editor concerning the article 'Association between rotavirus vaccination and risk of intussusception among neonates and infants: a systematic review and meta-analysis' (JAMA Netw Open. 2019;2(10):e1912458).

A recent meta-analysis investigating the association between intussusception (IS) and rotavirus (RV) vaccination demonstrated an absence of risk up to 2 years after vaccination. Meta-analyses including only randomized clinical trials are inadequate to identify a potential increased risk of rare adverse events such as IS. The study conducted failed to discuss relevant limitations. Additionally, the safety profiles of newer RV vaccines, evaluated in clinical studies with limited sample size, were considered comparable with that of the well-established and widely used RV vaccines, RotaTeq and Rotarix. We, therefore, re-emphasize that extensive and updated evidence from post-marketing surveillance indicates a slight increased risk of IS, mostly within 7 days of RV vaccination, with a benefit/risk profile assessment in favor of RV vaccination.

Role of healthcare practitioners in rotavirus disease awareness and vaccination - insights from a survey among caregivers.

An online survey was designed to assess awareness and understanding of Rotavirus (RV) gastroenteritis (RVGE), and knowledge and attitudes towards RV vaccination in Germany, Poland, Turkey, Indonesia, the Philippines and Thailand. Survey participants (n = 1500) comprised parents, expectant parents and guardians of children ≤5 years of age who have sole or joint responsibility for health and well-being decisions relating to their child, who were recruited from an online panel and provided their consent for study participation. Participants from most countries had a high level of awareness of RV infections (mean: 82%) and of those aware of RV, a mean of 61% participants were aware that RV was the most common cause of GE, however the majority (mean: 59%) were unaware that nearly every child would be infected with RVGE by the age of 5 years. Healthcare professional (HCP) recommendation was identified as the key driver for participants seeking vaccination (48%-75% of participants stated this reason, with results differing by country) followed by availability of RV vaccine in the national immunization program. Despite a high level of awareness of RVGE among participants, fostering knowledge regarding the difficulty of RVGE prevention, the risk of RV contraction and the associated serious consequences like dehydration is imperative to improve RV vaccination uptake. HCPs, being the primary influence on participants' decision on vaccination, are best suited to bridge existing knowledge gaps and recommend parents to vaccinate their children against RVGE.

Systematic review of the rotavirus infection burden in the WHO-EMRO region.

Rotavirus gastroenteritis imposes a heavy burden on low- and middle-income countries. The World Health Organization defines the Eastern Mediterranean region (WHO-EMRO) as a diverse area in terms of socioeconomic status and health indicators. Rotavirus vaccination has been introduced, at least partially, in 19 out of the 22 EM countries; however, vaccine coverage remains low, and data on rotavirus disease burden is scarce.Available data on rotavirus prevalence, seasonality, vaccination status, and genotype evolution was systematically compiled following a literature review that identified 165 relevant WHO-EMRO epidemiology studies published between 1990 and 2017.Although the infectious agents responsible for acute gastroenteritis vary over time, rotavirus remained the leading cause of acute gastroenteritis in children, as seen in 76.3% of reviewed publications. Younger children (<2 years old) were at higher risk and thus increased vaccination coverage and surveillance systems are required to reduce the rotavirus gastroenteritis burden in WHO-EMRO countries.

A review of recommendations for rotavirus vaccination in Europe: Arguments for change.

BACKGROUND: More than 10 years after the authorisation of two rotavirus vaccines of demonstrated efficacy and with a strongly positive benefit-risk profile, uptake in Europe remains low. Only 13 countries in Europe provide a fully-funded rotavirus universal mass vaccination (UMV) programme, three provide a partially-funded programme, and one provides full funding for a reduced programme targeting at-risk infants. Around 40% of countries in Europe currently have no existing recommendations for rotavirus vaccine use in children from the national government. METHODS: We provide an overview of the status of rotavirus vaccine recommendations across Europe and the factors impeding uptake. We consider the evidence for the benefits and risks of vaccination, and argue that cost-effectiveness and cost-saving benefits justify greater access to rotavirus vaccines for infants living in Europe. RESULTS: Lack of awareness of the direct and indirect burden caused by rotavirus disease, potential cost-saving from rotavirus vaccination including considerable benefits to children, families and society, and government/insurer cost constraints all contribute to complacency at different levels of health policy in individual countries. CONCLUSIONS: More than 10 years after their introduction, available data confirm the benefits and acceptable safety profile of infant rotavirus UMV programmes. Europe serves to gain considerably from rotavirus UMV in terms of reductions in healthcare resource utilization and related costs in both vaccinated subjects and their unvaccinated siblings through herd protection.