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Title: Predictors of vaccine virus replication, immune response and clinical protection following oral rotavirus vaccination in Malawian children
Author: Pollock, Louisa Elizabeth
ISNI:       0000 0004 7428 7411
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2018
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Background: Current rotavirus vaccines are least effective in low-income, high-burden countries. Reduced vaccine response is likely to be multifactorial. The aim of this thesis was to determine whether passively-acquired maternal antibody levels, oral polio vaccine (OPV) response and histo-blood group antigen (HBGA) phenotype predict vaccine virus replication, immune response and clinical protection in Malawian infants following oral administration of the monovalent human rotavirus vaccine (RV1). Methods: In a longitudinal cohort study, infants received two doses of RV1 at 6 and 10 weeks of age. Stool was collected on alternate days for 10 days post-vaccine to detect RV1 and OPV vaccine virus shedding by RT-PCR. Pre and post-vaccine serum rotavirus(RV)-specific IgA and IgG were determined by ELISA, with seroconversion defined as change from seronegative (RV-specific IgA < 20 u/mL) to seropositive (RV-specific IgA > 20U/mL) or > 4x rise in concentration in infants seropositive at baseline. HBGA phenotype was determined by salivary ELISA and confirmed by FUT2 genotyping. Infants with detectable of A, B, or H antigens in saliva were defined as secretors. Infants with detectable Lewis a or b antigens in saliva were defined as Lewis positive and those with undetectable Lewis antigens as Lewis negative. In a separate cross-sectional case-control study, vaccinated infants < 12 months with rotavirus gastroenteritis (RVGE) were compared to age-matched, vaccinated community and non-RVGE controls. Rotavirus detection and genotyping were confirmed by RT-PCR. Results: Following rotavirus immunisation, 104/202 (52%) of infants had detectable vaccine virus shedding and 47/196 (24%) achieved RV-specific IgA seroconversion. Infants with the highest levels of maternal rotavirus-specific IgG antibody had reduced likelihood of vaccine virus shedding (RR 0.44, 95%CI 0.27-0.72, p=0.001) and lower RV-specific IgA response. Linear correlation between RV-specific IgG and vaccine response was weak, suggesting a threshold effect. There was no correlation between quantitative rotavirus and OPV vaccine virus shedding, but some evidence of common patterns of OPV and RV1 response. Protective poliovirus type 3 neutralizing antibody titres at 6 weeks were associated with RV1 shedding in the 1st RV1 dose period (RR 2.24, 95%CI 1.25-4.0, p=0.007). OPV shedding in the 2nd RV1 dose period was associated with RV1 shedding (RR 2.0, 95%CI 1.0-3.8, p=0.04). All 14 infants who failed to attain protective serotype 3 poliovirus-specific neutralizing antibody titres also failed to attain rotavirus vaccine seroconversion. There was no association observed between any HBGA phenotype and overall likelihood of vaccine virus shedding or seroconversion. In a sub-study of 186 infants, HBGA phenotype determined genotype-specific susceptibility to rotavirus infection: secretor phenotype was strongly associated with P[8] RVGE (OR 7.8, 95%CI 1.8-33.7, p=0.005) and P[4]RVGE (OR 5.8. 95%CI 1.3-25.2, p=0.02) and Lewis negative phenotype was associated with P[6] infection (OR 3.0, 85%CI 1.3-6.7, p=0.008). Comparing 119 RVGE cases to 119 age-matched community controls, non-secretor phenotype was associated with decreased risk of clinical rotavirus vaccine failure (OR 0.40, 95%CI 0.2-0.8, p=0.005). RV-specific IgA > 90U/mL at time of presentation was associated with a 75% decrease in the odds of clinical vaccine failure. Infants with vaccine failure mounted a robust convalescent RV-specific IgA response. Conclusions: A threshold inhibitory effect of maternal antibody, together with the strong association of low RV-specific IgA and vaccine failure, suggests that booster dosing regimens could potentially improve RV1 effectiveness in Malawi. Further research is required to determine the optimal schedule. There was no evidence of direct competitive inhibition observed between OPV of RV1 vaccine virus shedding patterns. Common factors may predict response to both vaccines. Contrary to our hypothesis, non-secretor infants were at decreased risk of clinical vaccine failure, due to relative protection against common rotavirus strains. HBGA phenotype is unlikely to contribute to reduced rotavirus vaccine effectiveness in Malawi. New non-P[8] based vaccines are therefore unlikely to confer additional benefit based on the HBGA hypothesis.
Supervisor: Iturriza-Gomara, Miren Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral