Enhancing immune responses to oral vaccines: still an enigma
Authors: David A Sack
Journal: The Lancet Infectious Diseases (2019)

In The Lancet Infectious Diseases, James A Church and colleagues1Church JA Park EP Kirkpatrick BD et al.Interventions to improve oral vaccine performance: a systematic review and meta-analysis.Lancet Infect Dis. 2019; 19: 203-214Summary Full Text Full Text PDF Scopus (36) Google Scholar report the results of a systematic review and meta-analysis of studies on attempts to enhance the immune responses to oral vaccines, especially infants given oral polio vaccine (OPV) and oral rotavirus vaccine. The suboptimal immune responses to these oral vaccines in Africa and Asia has long been recognised, and it would seem there should be a reasonable explanation and a simple intervention that could improve effectiveness. This review, however, concludes that there are no simple solutions that could be applied generally for oral vaccines. OPV was highly successful in eliminating polio from North America and it was assumed that the vaccine would have a similar outcome in low-income countries. Unfortunately, this was not the case in India and other low-income countries.2John TJ Immunisation against polioviruses in developing countries.Rev Med Virol. 1993; 3: 149-160Crossref Scopus (31) Google Scholar More doses of vaccine were required to achieve similar response rates to those in North America, and cases of polio continued to occur even in areas of high OPV coverage. Similarly, rotavirus vaccines, which were highly efficacious in North and South America,3Ruiz-Palacios GM Perez-Schael I Velazquez FR et al.Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis.N Engl J Med. 2006; 354: 11-22Crossref PubMed Scopus (1552) Google Scholar, 4Vesikari T Matson DO Dennehy P et al.Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine.N Engl J Med. 2006; 354: 23-33Crossref PubMed Scopus (1581) Google Scholar showed lower efficacy in Africa5Madhi SA Cunliffe NA Steele D et al.Effect of human rotavirus vaccine on severe diarrhea in African infants.N Engl J Med. 2010; 362: 289-298Crossref PubMed Scopus (18) Google Scholar and Asia.6Zaman K Dang DA Victor JC 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; 376: 615-623Summary Full Text Full Text PDF PubMed Scopus (555) Google Scholar Now that the vaccines are used routinely, their effectiveness is confirmed, but at a lower rate in lower-income countries.7Zaman K Sack DA Neuzil KM et al.Effectiveness of a live oral human rotavirus vaccine after programmatic introduction in Bangladesh: a cluster-randomized trial.PLoS Med. 2017; 14: e1002282Crossref PubMed Scopus (42) Google Scholar Clearly, even with the lower efficacy, these vaccines provide a major public health benefit because the disease burden is so high; however, if there was a way to improve immunogenicity, these vaccines would be even more powerful. Many reasonable theories have been suggested as to why children in low-income countries have a weaker response to oral vaccines than do those in high-income countries.8Qadri F Bhuiyan TR Sack DA Svennerholm AM Immune responses and protection in children in developing countries induced by oral vaccines.Vaccine. 2013; 31: 452-460Crossref PubMed Scopus (76) Google Scholar The most common suggestions relate to interference by maternal antibody in serum or breast milk, intestinal parasitic infestations, micronutrient (especially zinc or vitamin A) or macronutrient malnutrition, concurrent enterovirus infection, and intestinal mucosal enteropathy. Considering the young age at immunisation, some of these explanations seem more likely than others. For example, parasitic infestations, micronutrient deficiencies, or even enteropathy would seem to be uncommon at this young age. Nevertheless, considering these potential mechanisms, controlled clinical trials have attempted to improve the immune responses to these vaccines. In short, Church and colleagues found that there was no general strategy that seems to substantially improve the serological responses to these oral vaccines. Of those tested, some would have been difficult to implement, such as avoiding breastfeeding for a few hours, but if the strategies had been effective, at least they would have provided insight into the causes of the suboptimal immune responses. Although there appears to be no simple intervention, there have been ways to mitigate the problem. Because trivalent OPV does not protect every infant, two changes to polio vaccine programmes have been made.9WHOPolio vaccines: WHO position paper—March, 2016.Wkly Epidemiol Rec. 2016; 91: 145-168PubMed Google Scholar First, OPV was changed from a trivalent to a bivalent vaccine by eliminating type 2 from the vaccine. Second, at least one dose of injected polio vaccine is to be given during infancy. Interestingly, despite suboptimal responses to OPV, infants respond well to injected polio vaccine1Church JA Park EP Kirkpatrick BD et al.Interventions to improve oral vaccine performance: a systematic review and meta-analysis.Lancet Infect Dis. 2019; 19: 203-214Summary Full Text Full Text PDF Scopus (36) Google Scholar and the bivalent vaccine appears to be more immunogenic than the trivalent vaccine that was used previously. Because serotype 2 virus has been eradicated, a vaccine for this type is no longer needed. These changes were important, not only to protect individual children, but also because they are crucial for polio's eradication. One strategy being considered for rotavirus is a supplemental dose of vaccine at age 9 months.10Zaman K Fleming JA Victor JC et al.Noninterference of rotavirus vaccine with measles-rubella vaccine at 9 months of age and improvements in antirotavirus immunity: a randomized trial.J Infect Dis. 2016; 213: 1686-1693Crossref PubMed Scopus (38) Google Scholar In many places, the peak incidence of rotavirus diarrhoea is between 9 and 18 months, and this later dose could increase protection during this high-risk period. When first studied, a late dose was not considered because of concern over intussusception, but the current vaccines have a low intussusception risk, which is probably even lower in previously immunised children. As with polio, there could be a role for an injectable rotavirus vaccine, which, either alone or in conjunction with oral vaccine, could improve protection.11Groome MJ Koen A Fix A et al.Safety and immunogenicity of a parenteral P2-VP8-P[8] subunit rotavirus vaccine in toddlers and infants in South Africa: a randomised, double-blind, placebo-controlled trial.Lancet Infect Dis. 2017; 17: 843-853Summary Full Text Full Text PDF PubMed Scopus (84) Google Scholar An injectable vaccine was not originally developed because it was thought that an oral vaccine would better stimulate intestinal immunity. However, rotavirus diarrhoea is mainly a disease of young children, and since natural infections stimulate immunity, it is possible that only short-term protection is needed and could be accomplished with an injectable vaccine. Finally, if new strategies are identified, they will still have to be practical to be included in routine immunisation programmes. A delayed dosing for rotavirus vaccine did seem to improve immune response, but this approach needs to be balanced against the potential of not immunising some infants who drop out early. Similarly, a 9-month oral rotavirus dose and an injectable rotavirus vaccine seem promising, but the logistical challenges and costs for these will need to be investigated. I declare no competing interests. Interventions to improve oral vaccine performance: a systematic review and meta-analysisMost strategies did not improve oral vaccine performance. Delaying RVV and reducing OPV valence should be considered within immunisation programmes to reduce global enteric disease. New strategies to address the gap in oral vaccine efficacy are urgently required. Full-Text PDF Open Access