Table 2.
Comparative analysis of rotavirus vaccine efficacy and effectiveness in pre-clinical trials.
| Vaccine | Seasonal Efficacy/Follow-up/Doses | Remark | |
|---|---|---|---|
| First-Year Follow-up | Second-Year Follow-up | ||
| North America and Europe | |||
| Rotarix® was tested against RVGE in infants from six different European countries | 87.1% efficacy against any SRVGE and 75–96% efficacy against the corresponding genotypes G1–G4 and G9 | 71.9% efficacy against any SRVGE and 69–84% efficacy against the corresponding G1–G4 and G9. About 85.6% efficacy against SRVGE and 77–97% efficacy against the corresponding G1–G4 and G9 | Observed combined efficacy against any SRVGE and SRVGE was 78.9% and 90.4% respectively. The combined efficacy against all-cause SRVGE and hospital admission was 49.6% and 71.5%, respectively [135]. Though similar reactogenic was observed in the tested groups, serious and nonserious adverse effects were reported, but no IS case in the USA and Canada [168]. |
| Rotarix® was evaluated for safety and immunogenicity | 95.8% efficacy against SRVGE and 74–100% against the G1–G4 and G9 | 2Ds of RV1 are well tolerated with a high vaccine “take”, highly immunogenic to induce IgA without side effect or interference with routine childhood vaccines [174]. | |
| RotaTeq® evaluated for efficacy and safety in >30,000 infants out of 70,000 infants’ enrolment for REST analysis in 5 European countries | 100% efficacy against SRVGE and 72% efficacy against any RVGE | 94.3% efficacy against SRVGE and 58.5% efficacy against any RVGE | RotaTeq® showed the efficacy of 98.3% and 68% respectively against SRVGE and all-cause of RVGE due to any serotype for the two rotavirus seasons in Europe. Further, 94.5% efficacy against RVGE hospitalisation and EV due to any serotype over 2 years of vaccination without any significant safety concern [121]. |
| Latin America | |||
| Rotarix® trial in 63,225 infants in 1-year Phase III trial from 11 Latin American and Finland | FDs produced 85% efficacy against SRVGE and hospitalisation, reaching 100% against VSRVGE with 45% efficacy in reducing any-cause of rotavirus diarrhoea hospitalisation | Two oral doses of the live attenuated G1P[8] HRV vaccine protected infants without associating with an increased risk of IS [127]. | |
| Rotarix® effectiveness in Bolivia | RV1 offered sustainable protection through two years of the life of Bolivian children, with similar VE against hospital admission <1 year and >1 year of age | RV1 offered significant protection against hospital admission for diarrhoea caused by diverse serotypes: G9P[8], G3P[8], G2P[4], and G9P[6], which are either partially and fully heterotypic to the G1P[8] vaccine [175]. This protection was sustained over two years of life against diverse serotypes different from the vaccine strain. | |
| Rotarix® introduction vs. reduction of all-cause diarrhoea death in Brazil, El Salvador, Mexico, Nicaragua, Panama, Venezuela, Bolivia, and Honduras | There was a significant reduction in all-cause diarrhoea mortality in the post-vaccination period among children <5 years old between 2006 and 2009 compared with the pre-vaccination period [176]. This reduction, 30–50%, was significant in all the vaccine adopter countries except Nicaragua. However, non-vaccine adopter countries (Argentina, Chile, Costa Rica, and Paraguay) showed a greater mortality reduction in the pre-vaccination period, 2002–2005 [176] | Significant reduction after post-vaccination in these countries was observed except in Panama, where this reduction was not observed. Concomitantly, countries such as Argentina, Chile, Costa Rica, and Paraguay were not using the vaccine at the time of this assessment [176]. Vaccine impact on the reduction of deaths was more than the hospitalisation [177]. | |
| Duration of protection offered by RotaTeq® in Nicaragua | Risk of rotavirus hospitalisation was two-fold lower in vaccinated children <1 year compared with ≥1 year | There was no significant reduction in rotavirus hospitalisation in the second year after the last vaccine dose | Waning immunity was suspected, and a booster dose was suggested in Nicaragua [178]. |
| RotaTeq® introduction vs. reduction of all-cause diarrhoea death rates in Mexico and Nicaragua | Significant reduction in all-cause diarrhoea mortality in <5 years between 2006 and 2009 when comparing postvaccination and pre-vaccination together | A significant reduction was observed in Mexico, but not in Nicaragua [176]. | |
| Africa | |||
| Rotarix® efficacy against severe diarrhoea | After the first year of follow-up, 61.2%, 58.7%, and 63.7% overall efficacy against SRVGE were observed in South Africa and Malawi combined. In South Africa, the efficacies of 2 and 3Ds were 72.2% and 81.5% and a pooled of 76.9%, while in Malawi, 49.2% and 49.7% with a pooled of 49.4% were respectively observed. Efficacy against all-cause SRVGE was 30.2%, and when pooled, South Africa was 44.1%, while Malawi was 25.1% [130] | There was a marginal reduction in vaccine efficacy in the second year of follow-up in Malawi. The 2Ds, 3Ds, and pooled efficacies against SRVGE were 2.6%, 33.1%, and 17.6% while against severe any-cause RVGE were 13.2%, 5.2%, and 9.3% respectively. There was 9.3% efficacy against all SRVGE, while the entire follow-up yielded 15.9% vaccine efficacy [179] | RV1 significantly reduced the incidence of RVGE among African infants during the first year of life. No difference in vaccine efficacy against G1 and non-G1 (G2, G8, G12) [180,181]. Madhi and co-workers observed a higher preventable episode of SRVGE/100 infants vaccinated/year in Malawi (6.7) than South Africa (4.2), though vaccine efficacy was lower in the former than the latter [130]. From Malawi, RV1 significantly reduced the incidence of SRVGE caused by diverse rotavirus strains and more episodes of SRVGE, and any SRVGE seemed to be prevented at 2Ds more than 3Ds, even after the entire follow-up [179]. Vaccine-acquired immunity seemed not to endure beyond the first year of vaccination. Three doses boost vs. 2Ds of RV1 in Malawi at the first year of follow-up produced 27.2% vs. 22.9% efficacies against all-cause SRVGE, while after the second year of follow-up, 5.2% vs. 13.2% efficacies were observed and the entire follow-up yielded 15.7% vs. 16% efficacies [179]. |
| RotaTeq® efficacy between 2007 and 2009 | Prevention of SRVGE in Ghana was 65%, Kenya 83.4%, Mali 1%, and overall was 64.2% | Prevention of SRVGE in Ghana was 29.4%, Kenya 54.7%, Mali 19.2% and overall was 19.6% | Overall efficacies of 30.5%, 39.3%, 40.7%, and 100% were observed against any severity, moderate-to-severe, severe, VSRVGE, respectively. GE was the most common adverse event associated with this vaccine, and this occurred within 14 days of any dose. There was no significant difference in this adverse events rate (0.6% each) between the vaccinated and the placebo. High IgA sero-response rates of 78.9%, 73.8%, and 82.5% were observed in Ghana, Kenya, and Mali, respectively, but very low serotype-response rates to G1–G4 and P1A[8]. Overall efficacy against moderate-to-severe RVGE was 55.5%, 63.9%, and 17.6% in Ghana, Kenya, and Mali, respectively. Generally, the efficacy of RV5 in sub-Sahara Africa was higher with higher severe cases of RVD prevented/100 vaccinated/year in the first year of follow-up than the second year, however, because of the intense mortality rates in Africa, the magnitude of prevented cases is very high than any other region [136]. Note: Infants with HIV infection were included in this study |
| RotaSIIL® efficacy assessed in 3508 infants from Niger | In a 2-stratum treatment (ITTP vs. PPP), the efficacy of 3Ds of BRV-PV against all RVGE (33% vs. 34.5%), against SRVGE (69.1% vs. 66.7%), against VSRVGE (77.4% vs. 78.8%), against all GE (−12.4% vs. −0.6%) against SGE (16.2% vs. 10.7%), and against VSGE (67.7% vs. 68%). Cases of SRVGE/100 infant vaccinated/year in the vaccine vs. placebo groups were 2.14 vs. 6.44 | At 66.7% efficacy, BRV-PV prevented 4.3 episodes of SRVGE/100 infants vaccinated/year. No significant difference in the adverse events and mortality rate. No IS cases. Efficacy increases with clinical severity. This vaccine offered protection against SRVGE resulting in mortality and morbidity of infants, and there is no need for cold storage facility (stable for 2 years at 37 °C or 6 months at 40 °C) [182]. | |
| Southeast Asia | |||
| RotaTeq® efficacy in 2036 recruited infants from Bangladesh and Vietnam | Overall efficacy against SRVGE in Bangladesh was 42.7% with the first-year follow-up of 45.7% while Vietnam was 63.9% with the first-year follow-up of 72.3% | The second-year follow-up for Bangladesh was 39.3%, and Vietnam was 64.6% | Overall efficacy of 42.5%, 48.3%, and 70% against any severity, SRVGE, and VSRVGE, respectively, for nearly 2 years of follow-up was reported. Vaccine efficacy increases with clinical severity. Higher efficacy was consistently found in Vietnam than in Bangladesh. However, efficacy against the VSRVGE (Vesikari score ≥ 15) was higher in Bangladesh because, before the vaccination, the infant mortality rate in Bangladesh (29.7/1000 live births) was twice Vietnam’s (14.7/1000 live births), and again the SRVGE cases were substantially higher in Bangladesh than Vietnam [57]. Pneumonia was one of the serious adverse events, which occurred within 14 days of any dose, and there was no significant difference in this adverse event between the vaccinated and the placebo [57]. |
| India | |||
| Rotavac® assessed for efficacy in India with 4532 infants ranging from 6 to 8-weeks-old | Efficacy of 56.4% against SRVGE with an incidence rate of 1.5 in vaccine vs. 3.2 in placebo groups. Six intussusception and 25 deaths in vaccine vs. 2 intussusception and 17 deaths in placebo groups were observed after the 3rd dose | Efficacy of 55.1% against SRVGE with an incidence rate of 1.3 in vaccine vs. 2.9 in placebo groups. Eight intussusception and 30 deaths in vaccine vs. 3 intussusception and 18 deaths in placebo groups were observed in the second year of follow-up | Whether from ITTP or PPP analysis, Rotavac® (116E) was effective and well-tolerated in Indian infants and maintained this efficacy in the second year after the 3Ds vaccination program. The reported adverse events were the same in the two groups—vaccine vs. placebo. IS occurred after 112 vs. 36 days at 1st year and 112–587 vs. 36–60 days at 2nd year, respectively. Increased seroconversion 4 weeks after the 3rd dose was observed, which suggested wildtype RVI in infants before the vaccination period [183] |
| RotaSIIL® assessed for efficacy in Phase III clinical trial in India with 3749 infants ranging from 6 to 8-weeks-old | Efficacy against VSRVGE was 60.5% with PPP analysis or 61.3% with ITTP analysis | Efficacy against VSRVGE was 54.7% with PPP analysis or 52.9% with ITTP analysis | Reactogenic response compared to placebo after 1st dose showed mild irritability (42.6% vs. 36.1%), severe fever ≥39.5–<40.5 °C (4 vs. 1 case), and LRTI (60 vs. 38 cases). All other adverse events were the same in the two arms. Overall reduction of SRVGE incidence was 1.7 cases/100 person/year in the ITTP. Generally low serum anti-rotavirus IgA seroresponses (33.6% vs. 9.7%), however, BRV-PV was well tolerated and a safe vaccine in Indian infants, but the efficacy is very low especially against SRVGE [61]. There was no vaccine interference with OPV because similar seroconversion to OPV was observed in the two arms. |
BRV-PV = bovine rotavirus pentavalent vaccine; D = dose; EV = emergency visit; FD = full doses; ITTP = intention-to-treat population; LRTI = lower respiratory tract infection; OPV = oral polio vaccine; PPP = per-protocol population; REST = rotavirus efficacy and safety trial; RoV = rotavirus vaccines; RVI = rotavirus infection; RVGE = rotavirus gastroenteritis; SRVD = severe rotavirus diarrhoea; SRVGE = severe rotavirus gastroenteritis; VSRVGE = very severe rotavirus gastroenteritis; VE = vaccine effectiveness. By the end of 2019, 80 countries (47 from GAVI-eligible countries) are using Rotarix®, 15 (4 from GAVI-eligible countries) RotaTeq®, 9 countries use both vaccines, and probably 3 countries with their national rotavirus vaccines making 98 countries (46 from GAVI-eligible countries). However, only 62 countries (29 from GAVI-eligible countries) have an available report on the RoV evaluation [141]. Summarily, the vaccine efficacy against SRVGE in the USA and Europe is 91%, in South America 80%, in Asia 50%, and in sub-Sahara Africa 46%. Correspondingly, the efficacy against all forms of diarrhoea-associated hospitalisation due to rotavirus is 94% in the USA and Europe, 84% in South America, 94% in Asia, and 58% in sub-Saharan Africa [126,184].