The Study On Immunogenicity And Influencing Factors Of Live Attenuated Rotavirus Vaccine

Rotavirus (RV) is the most common cause of infants’severe diarrhea around the world. Rotavirus infection is known as a "democratic disease", as it infects children in both developed and developing countries, leading to serious social and disease burden worldwide. But rotavirus infection causes higher under-five mortality rates in developing countries. Vaccination is the only effective way to prevent rotavirus diarrhea and reduce mortality. In recent ten years, the human strain rotavirus vaccine (Rotarix, GlaxoSmithKline, Belgium) and Bovine-human pentavalent reassortant rotavirus vaccine (RotaTeq, Merck & Co., US) are widely used in the world. Vaccine clinical trials and post market survey data showed that the live attenuated rotavirus vaccines were highly efficacious in developed countries, but not ideal in developing countries where they were most needed. It is urgent to find out the reasons of this phenomenon to improving the effectiveness of rotavirus vaccine in developing countries. A series of studies to explaining this phenomenon have been conducted, and the nutritional status of the vaccinated, intestinal flora, breastfeeding and the prevalence of viral strains were proposed to lead to the variable levels of protection conferred by rotavirus vaccine in different settings. They are not able to give a systemic and reasonable explanation, and the study from other aspects are eagerly needed.The immune system is a complex network. The factors leading to lower immune response in low-income countries may be not limited to the above. Therefore, in this study, the factors that may impair the immune response of rotavirus attenuated live vaccine were analyzed from the following three aspects:the maternal antibody, the genetic polymorphisms of human leukocyte antigen (HLA) and concomitant administration of oral poliomyelitis vaccine (OPV).In this study, healthy infants aged 6-13 weeks received three doses of the trivalent reassortant rotavirus vaccine with a interval of one month. Blood samples were collected before the administration of the first dose of vaccine and one month after the third dose of vaccine administration for G2, G3 and G4 types specific RV-IgA. According to whether the G type specific RV-IgA was seroconverted, infants were divided into two groups for each G type respectively. The pre-immunization sera were tested for maternal G2, G3 and G4 specific RV neutralizing antibodies (NT Ab). As a result, the seropositive rate and geometric mean titer (GMT) of pre-administration NT Ab display the following distribution characteristics:G4 type neutralizing antibody was the lowest (49.24%,12), followed by type G2 (82.95%,20), and type G3 was the highest (100%,91). Inversely, the GMT of post-administration G3 type specific RV-IgA was the lowest by 76U/mL, followed by G2 type 86U/mL and G4 type 90U/mL. The positive rate and GMT of any G type pre-administration NT Ab was lower in seroconverters group than that in non-seroconverters group. In addition to the G3 type, the differences of G2 and G4 types NT Ab between the two groups were statistical (P<0.05), indicating that the maternal antibody may interfere with immune response to live oral rotavirus vaccine.According to the age of the first dose of vaccine, the subjects were divided into two groups. The mean age was 8 weeks and 12 weeks, respectively. The differences in pre-administration NT Ab and post-administration RV-IgA between the two groups were statistical analyzed to investigate if the delaying schedule can eliminate the influence of maternal antibodies and enhance the immune response of vaccine. As a result, in addition to the seropositive rate of G2 and G3 type NT Ab, vaccinees aged 12 weeks had lower seropositive rate and GMT of pre-immunization NT Ab than infants aged 8 weeks. Inversely, the seroconversion rate and GMT of RV-IgA were higher in the group aged 12 weeks except the GMT of G3 type, but did not show statistical significance. In conclusion, maternal antibodies could gradually decay over time. In our country, it may be helpful in eliminating the influence of maternal antibodies to delay the schedule to 12 weeks of age, but the study on more age group is needed.On the basis of the above vaccination population, infants with any G type specific RV-IgA seroconverted were classified as seroconverters group. Conversely, infants whose all of G types specific RV-IgA didn’t seroconvert were classified as nonseroconverters group.55 and 41 subjects belonging to seroconverters and nonseroconverters group respectively were randomly selected to detect the HLA-A,-B,-C,-DRB1 and DQB1 loci genotype by sequence-based typing (SBT) method. The frequencies of each HLA allele, haplotype and supertype were compared between the two groups by statistical analysis to assess the association of polymorphisms of HLA and immune response to rotavirus vaccine. The results showed that the more statistically frequent HLA-B*40:01 was found among seroconverters group infants than nonseroconverters, suggesting that it may be associated with non-response of rotavirus vaccine.To evaluate if concomitant administration of OPV affect the immune responses and seroconversion to the vaccine, Rotarix was studied as the candidate vaccine. All of the vaccinees received two doses of Rotarix with the normal schedule. According to the administration of OPV, the vaccines were divided into two groups. Concomitant administration was defined as Rotarix and OPV given on the same day; staggered administration as Rotarix and OPV given≥1 day apart. Blood samples were collected before the administration of the first dose of vaccine, one month and one year after the second dose of vaccine administration for. The differences of RV-IgA seroconversion and GMT between the two groups were analyzed by statistical method. In the respect of RV-IgA in one month after vaccination, infants who received Rotarix and OPV concomitantly were less likely to seroconvert (63.95%) than those who received both vaccines staggered≥1 day (73.84%, P=0.033). A higher RV-IgA GMT, not achieving statistical significance, in staggered administration group was observed (97:90). Concomitant administration of OPV seems to lower Rotarix seroconversion without influencing the level of antibody in group. About RV-IgA in one year after immunization, infants staggered administrated had significantly higher seroconversion rate and GMT (P <0.05). The seroconversion rate and GMT decreased more significantly in concomitant administration group, indicating that concomitant administration would affect the maintain of RV-IgA.In conclusion, the interrelated factors were illustrated in this study. The maternal antibody, genetic polymorphisms of HLA and concomitant administration of OPV were confirmed to be responsible for the poorer effectiveness and immunogenicity of RV vaccine in developing countries. It has a certain reference value for the research and development of the new rotavirus vaccine in the developing countries, the design of clinical trials and the formulation of the immunization program.