Rotavirus vaccines in developing countries: The potential impact, implementation challenges, and remaining questions

doi:10.1016/j.vaccine.2011.10.007

Vaccine

Volume 30, Supplement 1, 27 April 2012, Pages A3-A6

https://doi.org/10.1016/j.vaccine.2011.10.007 Get rights and content

Abstract

Diarrhoeal disease is one of the commonest causes of death in children, especially in developing countries in Africa and Asia. Rotavirus has been consistently identified as the commonest pathogen associated with severe diarrhoea. Hence, the availability of vaccines against this organism provides the opportunity to reduce child mortality. Data from efficacy trials in developing countries in Africa and Asia showed that the vaccine efficacy was lower than that observed in other countries. Nevertheless, the vaccines are expected to be of significant benefit in high mortality countries in these regions. While the reports published in this supplement add to our understanding about the performance of these vaccines in developing countries in these regions, questions remain over the overall impact of these vaccines when used in national programmes of developing countries in Africa and Asia, the optimal vaccination schedules and the impact of age restrictions for vaccine use on immunization coverage. Additional research is required to improve understanding on the performance of these vaccines in developing countries in Africa and Asia and measures that may improve performance. Data that will assist in the definition of the optimal immunization schedule and possibly allow relaxation of the age restrictions for vaccine use may help in enhancing the impact of the vaccines in these countries. Finally, disease surveillance and studies are required to document the impact of vaccination and monitor changes in disease epidemiology.

Highlights

► Rotavirus diarrhoea is an important cause of childhood morbidity and mortality. ► Data are still required to define optimal vaccination schedule and document the impact of rotavirus vaccine in Africa and Asia. ► Programmatic challenges related to the age restrictions for delivering vaccines might affect the overall impact of vaccines. ► Surveillance is required to monitor for strain changes that may alter vaccine effectiveness.

Section snippets

The impact of rotavirus vaccines in high child mortality populations

It is assumed that despite the lower observed efficacy of the current vaccines, they are likely to prevent more cases of severe disease and deaths in populations with high child mortality rates. However, the magnitude of the impact of these vaccines in these populations still needs to be fully documented. The trend towards greater efficacy against the more severe forms of rotavirus disease observed in several studies, including those published in this supplement (Breiman et al. and Tapia et

The optimal vaccination schedule in developing countries

To be optimally effective and cost-effective, a vaccination schedule should aim to induce immunity with the fewest number of doses before a sizeable proportion of the target population acquires natural infection. In developing countries where natural infection occurs early, completion of the immunization schedule early in infancy is desirable though programmatically challenging. From a programmatic perspective, it is easier if the vaccine doses are delivered at the same contact as with other

Intussusception, age restrictions for vaccination and related programmatic challenges

In view of the increased risk of intussusception observed with the older rhesus reassortant rotavirus vaccine (Rotashield^®), the trials with the newer rotavirus vaccines restricted its use to younger infants in whom the natural risk of intussusception is lower. Since intussusception was more often associated with the first dose, delivery of the first dose was restricted to children 6–12 weeks (RotaTeq^®) or 6–13 weeks (Rotarix™) [15], [16] of age and the labelled indications restrict the use of

Monitoring changes in rotavirus strains and interpreting the results

Data from developing countries in Asia and Africa show greater strain diversity than has been described in industrialized countries [20]. A review paper in this supplement (Miles et al.) describes the strain diversity of rotavirus in Bangladesh, India and Pakistan and also refers to the reports of the emergence of reassortant zoonotic strains in the region. The implications of strain diversity on vaccine efficacy are not fully understood, since available data show that the current vaccines

Conclusions

Rotavirus diarrhoea is an important cause of childhood morbidity and mortality world wide and particularly so in developing countries with high child mortality. Data on rotavirus diarrhoea and the efficacy of vaccination in developing countries is rapidly increasing, and there is increasing evidence to suggest that the vaccines will have a significant effect on childhood morbidity and mortality, despite the lower efficacy of the vaccines, in developing country populations in Asia and Africa.

References (21)

R.E. Black et al.
Global, regional, and national causes of child mortality in 2008: a systematic analysis
Lancet
(2010)
G.E. Armah et al.
Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in sub-Saharan Africa: a randomised, double-blind, placebo-controlled trial
Lancet
(2010)
K. Zaman et al.
Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in Asia: a randomised, double-blind, placebo-controlled trial
Lancet
(2010)
A.D. Steele et al.
Co-administration study in South African infants of a live-attenuated oral human rotavirus vaccine (RIX4414) and poliovirus vaccines
Vaccine
(2010)
A. Clark et al.
Timing of children's vaccinations in 45 low-income and middle-income countries: an analysis of survey data
Lancet
(2009)
J.P. Buttery et al.
Intussusception following rotavirus vaccine administration: post-marketing surveillance in the National Immunization Program in Australia
Vaccine
(2011)
U.D. Parashar et al.
Global mortality associated with rotavirus disease among children in 2004
J Infect Dis
(2009)
World Health Organization
Global vaccination update, 2009
Wkly Epidemiol Rec
(2010)
M.M. Patel et al.
Real-world impact of rotavirus vaccination
Pediatr Infect Dis J
(2011)
V. Richardson et al.
Effect of rotavirus vaccination on death from childhood diarrhea in Mexico
N Engl J Med
(2010)

There are more references available in the full text version of this article.

Cited by (34)

Safety and immunogenicity of human neonatal RV3 rotavirus vaccine (Bio Farma) in adults, children, and neonates in Indonesia: Phase I Trial
2021, Vaccine
Citation Excerpt :
Inconsistent with causal association to immunization, and D). Unclassifiable [27]. Among neonates, immunogenicity was be evaluated at baseline and 28 days after the first and third doses by measurement of serum IgA using enzyme-linked immunosorbent assay (ELISA) and serum neutralizing antibody (SNA) methods that were developed at MCRI, Australia [13].
Despite safe and effective WHO prequalified rotavirus vaccines, at least 84 million children remain unvaccinated. A birth dose schedule of the RV3-BB vaccine was reported to be highly efficacious against severe rotavirus disease in Indonesian infants and is under further development at PT Bio Farma, Indonesia. The aim is to develop a rotavirus vaccine starting from birth that could improve the implementation, safety, and effectiveness of vaccines.
A multi-site phase I study of a human neonatal RV3 rotavirus vaccine (Bio Farma) in adults, children, neonates in Indonesia from April 2018 to March 2019. The adult and child cohorts were open-labeled single-dose, while the neonatal cohort was randomized, double-blind, and placebo-controlled three-doses at the age of 0–5 days, 8–10 weeks, and 12–14 weeks. The primary objective was to assess the safety of vaccines with the immunogenicity and vaccine virus fecal shedding as the secondary endpoints in neonates.
Twenty-five adults, 25 children, and 50 neonates were recruited, and all but one in the neonatal cohort completed all study procedures. Three serious adverse events were reported (1 adult & 2 neonates), but none were assessed related to investigational product (IP). The neonatal vaccine group had a significantly higher positive immune response (cumulative seroconverted SNA and IgA) 28 days after three doses than those in the placebo group (72% vs. 16.7%, respectively). The GMT of serum IgA in the vaccine group was significantly higher at post IP dose 1 (p < 0.05) and post IP dose 3 (p < 0.001) compared to the placebo group.
The trial results show that the RV3 rotavirus vaccine (Bio Farma) is well tolerated in all participant cohorts (adults, children, and neonates). Three doses of this vaccine administered in a neonatal schedule were immunogenic. These promising results support further clinical development of the RV3 rotavirus vaccine (Bio Farma).
Rotavirus activates dendritic cells derived from umbilical cord blood monocytes
2016, Microbial Pathogenesis
Rotavirus is the most common cause of acute infectious diarrhea in human neonates and infants. However, the studies aimed at dissecting the anti-virus immune response have been mainly performed in adults. Dendritic cells (DCs) play a crucial role in innate and acquired immune responses. Therefore, it is very important to determine the response of neonatal and infant DCs to rotavirus and to compare it to the response of adult DCs. Thus, we determined the response of monocyte-derived DCs from umbilical cord blood (UCB) and adult peripheral blood (PB) to rotavirus in vitro. It was found that the rotavirus and its genome, composed of segmented doubled stranded RNA (dsRNA), induced the activation of neonatal DCs, as these cells up-regulated the levels of CD40, CD86, MHC II, TLR-3 and TLR-4, the production of cytokines IL-6, IL-12/23p40, IL-10, TGF-β (but not of IL-12p70), and the message for TNF-α and IFN-β. This activation enabled the neonatal DCs to induce a strong proliferation of allogeneic CD4⁺ T cells and the production of IFN-γ. Moreover, neonatal DCs could be infected by rotavirus and sustain its replication. Neonatal DCs had a similar response as adult DCs towards rotavirus and its genome. However, adult DCs had a biased pro-inflammatory response compared to neonatal DCs, which showed a biased regulatory profile, as they produced higher levels of IL-10 and TGF-β, and were less efficient in inducing a Th1 type response. So it can be concluded that rotavirus and its genome can induce the activation of neonatal DCs in spite of their tolerogenic bias.
Synthetic biology design to display an 18kDa rotavirus large antigen on a modular virus-like particle
2015, Vaccine
Citation Excerpt :
Two approved live attenuated rotavirus vaccines are available; namely Rotarix™ (GlaxoSmithKline) and RotaTeq™ (Merck). Existing vaccines have significant limitations in the countries of greatest need [9,10]. The affordability of these vaccines in low-income countries and the increased risk of intussusception associated with rotavirus vaccines underpin ongoing research for the next generation of low-cost and safe subunit rotavirus vaccine.
Virus-like particles are an established class of commercial vaccine possessing excellent function and proven stability. Exciting developments made possible by modern tools of synthetic biology has stimulated emergence of modular VLPs, whereby parts of one pathogen are by design integrated into a less harmful VLP which has preferential physical and manufacturing character. This strategy allows the immunologically protective parts of a pathogen to be displayed on the most-suitable VLP. However, the field of modular VLP design is immature, and robust design principles are yet to emerge, particularly for larger antigenic structures. Here we use a combination of molecular dynamic simulation and experiment to reveal two key design principles for VLPs. First, the linkers connecting the integrated antigenic module with the VLP-forming protein must be well designed to ensure structural separation and independence. Second, the number of antigenic domains on the VLP surface must be sufficiently below the maximum such that a “steric barrier” to VLP formation cannot exist. This second principle leads to designs whereby co-expression of modular protein with unmodified VLP-forming protein can titrate down the amount of antigen on the surface of the VLP, to the point where assembly can proceed. In this work we elucidate these principles by displaying the 18.1 kDa VP8* domain from rotavirus on the murine polyomavirus VLP, and show functional presentation of the antigenic structure.
Impact of vaccination on the molecular epidemiology and evolution of group A rotaviruses in Latin America and factors affecting vaccine efficacy
2015, Infection, Genetics and Evolution
Citation Excerpt :
During this time period, a study found that the effectiveness of 3 doses of RV5 against rotavirus disease requiring admission or treatment with intravenous rehydration was 46% (95% CI, 18–64%) and that a single RV strain (G2P[4]) was identified in 88% of the RV cases (Patel et al., 2009). Whether this reduced efficacy was associated with the circulation of the G2P[4] genotype, which is only partially included in the vaccine, was unclear as efficacy of RV vaccines has in general been lower in developing countries (Cherian et al., 2012). Further RV surveillance studies carried out in Nicaragua at hospital level showed that RV5 did not substantially alter the historical pattern of seasonal fluctuation, as G2P[4] was barely detected following its predominant period (2007–2008) (Becker-Dreps et al., 2014b; Bucardo et al., 2015, 2012).
Despite high rotavirus (RV) vaccine coverage (∼83%) and good effectiveness (∼77%) against RV-diarrhea hospitalization, RV is still contributing to the burden of diarrhea that persists in hospital settings in several Latin American countries, where RV vaccination is being implemented. Due to the extensive genomic and antigenic diversity, among co-circulating human RV, a major concern has been that the introduction of RV vaccination could exert selection pressure leading to higher prevalence of strains not included in the vaccines and/or emergence of new strains, thus, reducing the efficacy of vaccination. Here we review the molecular epidemiology of RV in Latin America and explore issues of RV evolution and selection in light of vaccination. We further explore etiologies behind the large burden of diarrhea remaining after vaccination in some countries and discuss plausible reasons for vaccine failures.
G1P[8] species A rotavirus over 27years - Pre- and post-vaccination eras - in Brazil: Full genomic constellation analysis and no evidence for selection pressure by Rotarix® vaccine
2015, Infection, Genetics and Evolution
Citation Excerpt :
Furthermore, studies carried out in Australia, Austria, Brazil and El Salvador reported a reduction in RVA disease and GA cases in both unvaccinated and vaccinated cohorts, suggesting that the reduction of RVA transmission by the vaccinated population could benefit the unvaccinated members of the community (Patel et al., 2012). It is not known what determines the difference observed in the vaccine efficacy in developed and developing countries, and a few possibilities were postulated: differences in age, nutrition status, host genetics or other clinic-epidemiological information, as recently suggested in other studies (Cherian et al., 2012; Imbert-Marcille et al., 2014; Nordgren et al., 2014; Rongsen-Chandola et al., 2014). The study reports for the first time the 11 genome segment analysis from G1P[8] clinical strains collected in a time period of 27 years in different Brazilian regions in order to investigate how this genotype evolved in Brazil over three decades of investigation.
Epidemiological data on species A rotavirus (RVA) infections have demonstrated the genetic diversity of strains circulating worldwide. Many G and P genotype combinations have been described over the years, varying regionally and temporally, especially in developing countries. However, the most common G and P genotype combinations identified in RVA human strains worldwide are G1P[8], G2P[4], G3P[8], G4P[8] and G9P[8]. RVA genotype G1P[8] strains are responsible for more than 50% of child infections worldwide and component of the two vaccines (Rotarix® [RV1] and RotaTeq® [RV5]) licensed globally. For a better understanding of the evolutionary mechanisms of this genotype in Brazil, phylogenetic analyses based on the 11 RVA genome segments (genomic constellation) from 90 G1P[8] RVA strains collected in two eras – (i) pre-vaccination with RV1 (1996–February 2006); (ii) post-vaccination (March 2006–2013) – in different Brazilian states were performed. The results showed the Wa-like genomic constellation of the Brazilian G1P[8] strains with a I1-R1-C1-M1-A1-N1-T1-E1-H1 specificity, except for two strains (rj14055-07 and ba19030-10) that belong to a I1-R1-C1-M1-A1-N1-T3-E1-H1 genomic constellation, evidencing the occurrence of reassortment (Wa-like × AU-1-like) of the NSP3 gene. Reassortment events were also demonstrated between Brazilian G1P[8] strains and the RV1 vaccine strain in some genes in vaccinated and unvaccinated children. VP7 and VP8* antigenic site analysis showed that the amino acid substitutions observed in samples collected after the introduction of RV1 in Brazil were already detected in samples collected in the 1980s and 1990s, suggesting that mass Brazilian RV1 vaccination had no impact on the diversity observed inside antigenic sites for these two proteins.
Association of serum antibodies with protection against rotavirus infection and disease in South Indian children
2014, Vaccine
Citation Excerpt :
Currently, two live oral rotavirus vaccines (Rotarix [RV1] GSK biologicals and Rotateq [RV5] Merck & Co.) have been successfully evaluated in large-scale clinical trials, are licensed in over 100 countries and are in routine use in over 40 countries [3,4]. However, both vaccine protection and immunogenicity is considerably reduced in middle and lower income countries compared to high income settings [5–7]. Past studies have attempted to identify how serum antibodies protect against natural rotavirus infections.
Serum antibodies play an important role in natural protection from rotavirus infection and disease, but conflicting estimates of association have emerged from epidemiological studies in different geographical settings. In this study, we aim to assess the relationship between pre-existing serum immunoglobulin (Ig)G and IgA titers with protection against rotavirus infection and disease in a birth cohort of Indian children. Children were recruited at birth and followed up for 36 months. Stool samples were collected every 2 weeks and during episodes of diarrhea and serum samples were obtained at least every 6 months. The incidence rate of rotavirus infection and diarrhea was 0.9 (95% CI: 0.88, 0.99) and 0.2 (95% CI: 0.19, 0.25) episodes per child year, respectively. The risk of rotavirus infection and diarrhea decreased with age, while antibody titers (IgG and IgA) increased with age. After adjusting for age and number of previous infections, higher levels of IgG and IgA were independently associated with reduced risk of rotavirus infection. However, we did not find a clear association of IgG or IgA with rotavirus diarrhea risk or a threshold level of protection. The study supports a correlation of serum antibodies in reducing the risk of rotavirus infections, however the potential of serum antibody titer as a correlate of protection is not clear for children in lower income settings.

View all citing articles on Scopus

^☆: The authors are staff members of the World Health Organization. The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions, policy or views of the World Health Organization.

View full text

Rotavirus vaccines in developing countries: The potential impact, implementation challenges, and remaining questions☆

Abstract

Highlights

Section snippets

The impact of rotavirus vaccines in high child mortality populations

The optimal vaccination schedule in developing countries

Intussusception, age restrictions for vaccination and related programmatic challenges

Monitoring changes in rotavirus strains and interpreting the results

Conclusions

Lancet

Lancet

Lancet

Vaccine

Lancet

Vaccine

Global mortality associated with rotavirus disease among children in 2004

J Infect Dis

Global vaccination update, 2009

Wkly Epidemiol Rec

Real-world impact of rotavirus vaccination

Pediatr Infect Dis J

Effect of rotavirus vaccination on death from childhood diarrhea in Mexico

N Engl J Med