A randomized Phase III clinical trial to assess the efficacy of a bovine-human reassortant pentavalent rotavirus vaccine in Indian infants

Prasad S Kulkarni, Sajjad Desai, Tushar Tewari, Anand Kawade, Nidhi Goyal, Bishan Swarup Garg, Dinesh Kumar, Suman Kanungo, Veena Kamat, Gagandeep Kang, Ashish Bavdekar, Sudhir Babji, Sanjay Juvekar, Byomkesh Manna, Shanta Dutta, Rama Angurana, Deepika Dewan, Abhijeet Dharmadhikari, Jagdish K Zade, Rajeev M Dhere, Alan Fix, Maureen Power, Vidyasagar Uprety, Varsha Parulekar, Iksung Cho, Temsunaro R Chandola, Vikash K Kedia, Abhishek Raut, Jorge Flores, SII BRV-PV author group, Hanif Shaikh, Lalit Gupta, Rakesh Patil, Mohd Aslam, Alok Arya, Farhana Rafiqi, Subodh S Gupta, Chetna H Maliye, P V Bahulekar, Kiran Bala, Tajali Nazir Shora, Shahid Hussain, Mihir Kumar Bhattacharya, Ashis K Mukhopadhyay, Dilip Kumar Pal, Jayanta Saha, Ranjitha S Shetty, Muralidhar M Kulkarni, Chythra V Raj, Prasad S Kulkarni, Sajjad Desai, Tushar Tewari, Anand Kawade, Nidhi Goyal, Bishan Swarup Garg, Dinesh Kumar, Suman Kanungo, Veena Kamat, Gagandeep Kang, Ashish Bavdekar, Sudhir Babji, Sanjay Juvekar, Byomkesh Manna, Shanta Dutta, Rama Angurana, Deepika Dewan, Abhijeet Dharmadhikari, Jagdish K Zade, Rajeev M Dhere, Alan Fix, Maureen Power, Vidyasagar Uprety, Varsha Parulekar, Iksung Cho, Temsunaro R Chandola, Vikash K Kedia, Abhishek Raut, Jorge Flores, SII BRV-PV author group, Hanif Shaikh, Lalit Gupta, Rakesh Patil, Mohd Aslam, Alok Arya, Farhana Rafiqi, Subodh S Gupta, Chetna H Maliye, P V Bahulekar, Kiran Bala, Tajali Nazir Shora, Shahid Hussain, Mihir Kumar Bhattacharya, Ashis K Mukhopadhyay, Dilip Kumar Pal, Jayanta Saha, Ranjitha S Shetty, Muralidhar M Kulkarni, Chythra V Raj

Abstract

Rotavirus is the most common cause of moderate-to-severe infant diarrhoea in developing countries, resulting in enormous morbidity, mortality, and economic burden. A bovine-human reassortant pentavalent rotavirus vaccine (BRV-PV) targeting the globally most common strains was developed in India and tested in a randomized, double-blind, placebo-controlled end-point driven Phase III efficacy clinical trial implemented at six sites across India. Infants 6 to 8weeks of age were randomized (1:1) to receive three oral doses of BRV-PV or placebo at 6, 10, and 14weeks of age along with routine vaccines. Home visit surveillance was conducted to detect severe rotavirus gastroenteritis (SRVGE) and safety outcomes until the children reached two years of age. A total of 3749 infants received BRV-PV while 3751 received placebo. At the time of the primary end-point (when the minimum number of cases needed for analysis were accrued) the vaccine efficacy against SRVGE was 36% (95% CI 11.7, 53.6, p=0.0067) in the per protocol (PP) analysis, and 41.9% (95% CI 21.1, 57.3, p=0.0005) in the intent to treat (ITT) analysis. Vaccine efficacy over the entire follow-up period (until children reached two years of age) was 39.5% (95% CI 26.7, 50, p<0.0001) in the PP analysis and 38.8% (95% CI, 26.4, 49, p<0.0001) in the ITT analysis. Vaccine efficacy against the very severe rotavirus cases (VSRVGE, Vesikari score≥16) was 60.5% (95% CI 17.7, 81, p=0.0131) at the time of the primary analysis and 54.7% (95% CI 29.7, 70.8, p=0.0004) for the complete follow-period in the PP population. The incidence of solicited, unsolicited, and serious adverse events were similar in both the vaccine and placebo groups. Likewise, the number of intussusceptions and deaths were similar between both groups. Thus, BRV-PV is an effective, well tolerated and safe vaccine in Indian infants. (Trial registration: Clinical Trials.Gov [NCT 02133690] and Clinical Trial Registry of India [CTRI/2013/05/003667]).

Trial registration: ClinicalTrials.gov NCT02133690.

Keywords: Efficacy; Infants; Rotavirus gastroenteritis; Safety; Vaccine.

Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Fig. 1
Fig. 1
Study flowchart.
Fig. 2
Fig. 2
Relationship between Vesikari severity score and corresponding vaccine efficacy.

References

    1. Tate JE, Burton AH, Boschi-Pinto C, Parashar UD. World Health organization–coordinated global rotavirus surveillance network. Global, regional, and national estimates of rotavirus mortality in children 5 years of age, 2000–2013. Clin Infect Dis 2016;62(Suppl. 2):S96–S105.
    1. John J., Sarkar R., Muliyil J., Bhandari N., Bhan M.K., Kang G. Rotavirus gastroenteritis in India, 2011–2013: revised estimates of disease burden and potential impact of vaccines. Vaccine. 2014;32(Suppl 1):A5–A9.
    1. Rotavirus webpage. World Health Organization website. Available at: [date accessed April 14, 2017].
    1. Global Advisory Committee on Vaccine Safety, 11–12 June 2014. Wkly Epidemiol Rec 2014;89(29):325–35.
    1. Bhandari N., Rongsen-Chandola T., Bavdekar A. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, double-blind, placebo-controlled trial. Lancet. 2014;383(9935):2136–2143.
    1. Clements-Mann M.L., Dudas R., Hoshino Y. Safety and immunogenicity of live attenuated quadrivalent human-bovine (UK) reassortant rotavirus vaccine administered with childhood vaccines to infants. Vaccine. 2001;19(32):4676–4684.
    1. Clements-Mann M.L., Makhene M.K., Mrukowicz J. Safety and immunogenicity of live attenuated human-bovine (UK) reassortant rotavirus vaccines with VP7-specificity for serotypes 1, 2, 3 or 4 in adults, children and infants. Vaccine. 1999;17(20–21):2715–2725.
    1. Vesikari T., Karvonen A.V., Majuri J. Safety, efficacy, and immunogenicity of 2 doses of bovine-human (UK) and rhesus-rhesus-human rotavirus reassortant tetravalent vaccines in Finnish children. J Infect Dis. 2006;194(3):370–376.
    1. Zade J.K., Kulkarni P.S., Desai S.A., Sabale R.N., Naik S.P., Dhere R.M. Bovine rotavirus pentavalent vaccine development in India. Vaccine. 2014;32(Suppl 1):A124–A128.
    1. World Health Organization. The treatment of diarrhoea: a manual for physicians and other senior health workers. [date accessed: July 3, 2017].
    1. Ruuska T., Vesikari T. Rotavirus disease in Finnish children: use of numerical scores for clinical severity of diarrhoeal episodes. Scand J Infect Dis. 1990;22(3):259–267.
    1. Ward R.L., Bernstein D.I., Young E.C., Sherwood J.R., Knowlton D.R., Schiff G.M. Human rotavirus studies in volunteers: determination of infectious dose and serological response to infection. J Infect Dis. 1986;154:871–880.
    1. Bines, Kohl JE, KS the Brighton Collaboration Intussusception Working Group Acute intussusception in infants and children as an adverse event following immunization: case definition and guidelines of data collection, analysis, and presentation. Vaccine. 2004;22:569–574.
    1. World Health Organization. Management of severe malnutrition: a manual for physicians and other senior health workers. Geneva; 1999.
    1. Manual of rotavirus detection and characterization methods (WHO/IVB/08.17). Geneva: World Health Organization; 2009.
    1. World Health Organization. Polio laboratory manual. 4th ed., WHO/IVB/04.10, and supplement to the WHO polio laboratory manual. Geneva, Switzerland: World Health Organization; 2004.
    1. Vesikari T., Matson D.O., Dennehy P. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med. 2006;354:23–33.
    1. Vesikari T., Karvonen A., Puustinen L. Efficacy of RIX4414 live attenuated human rotavirus vaccine in Finnish infants. Pediatr Infect Dis J. 2004;23:937–943.
    1. Armah G.E., Sow S.O., Breiman R.F. 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;376(9741):606–614.
    1. Zaman K., Dang D.A., Victor J.C. 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(9741):615–623.
    1. Madhi S.A., Cunliffe N.A., Steele D. Effect of human rotavirus vaccine on severe diarrhea in African infants. N Engl J Med. 2010;362:289–298.
    1. Isanaka S., Guindo O., Langendorf C. Efficacy of a low-cost heat-stable oral rotavirus vaccine in niger. N Engl J Med. 2017;376:1121.
    1. Patel M., Shane A.L., Parashar U.D., Jiang B., Gentsch J.R., Glass R.I. Oral rotavirus vaccines: how well will they work where they are needed most? J Infect Dis. 2009;200(Suppl 1):S39–S48.
    1. Bhandari N., Rongsen-Chandola T., Bavdekar A. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian children in the second year of life. Vaccine. 2014;11(32 Suppl 1):A110–A116.
    1. Bauchau V., Van Holle L., Mahaux O., Holl K., Sugiyama K., Buyse H. Post-marketing monitoring of intussusception after rotavirus vaccination in Japan. Pharmacoepidemiol Drug Saf. 2015;24(7):765–770.
    1. Leino T., Ollgren J., Strömberg N., Elonsalo U. Evaluation of the intussusception risk after pentavalent rotavirus vaccination in Finnish infants. PLoS One. 2016;11(3):e0144812.
    1. Stowe J., Andrews N., Ladhani S., Miller E. The risk of intussusception following monovalent rotavirus vaccination in England: a self-controlled case-series evaluation. Vaccine. 2016;34(32):3684–3689.
    1. Noel G., Minodier P., Merrot T. Intussusception risk after rotavirus vaccination in U.S. infants. N Engl J Med. 2014;370(18):1766.
    1. Kompithra R.Z., Oaul A., Manoharan D. Immunogenicity of a three and five doses of oral rotavirus vaccine (RIX4414) schedule in South Indian infants. Vaccine. 2014;32S:A129–A133.
    1. Zaman K., Sack D.A., Yunus M. Successful co-administration of a human rotavirus and oral poliovirus vaccines in Bangladeshi infants in a 2-dose schedule at 12 and 16 weeks of age. Vaccine. 2009;27(9):1333–1340.
    1. Patel M., Steele A.D., Parashar U.D. Influence of oral polio vaccines on performance of the monovalent and pentavalent rotavirus vaccines. Vaccine. 2012;30(Suppl1):A30–A35.
    1. Matthias D.M., Robertson J., Garrison M.M., Newland S., Nelson C. Freezing temperatures in the vaccine cold chain: a systematic literature review. Vaccine. 2007;25(20):3980–3986.
    1. Nelson C., Froes P., Van Dyck A.M., Chavarría J., Boda E., Coca A. Monitoring temperatures in the vaccine cold chain in Bolivia. Vaccine. 2007;25(3):433–437.
    1. Guichard S., Hymbaugh K., Burkholder B., Diorditsa S., Navarro C., Ahmed S. Vaccine wastage in Bangladesh. Vaccine. 2010;28(3):858–863.
    1. Murhekar M., Dutta S., Kapoor A.N., Bitragunta S., Dodum R., Ghosh P. Frequent exposure to suboptimal temperatures in vaccine cold-chain systems in India: results of temperature monitoring in 10 states. Bull World Health Org. 2013;91:906–913.
    1. World Health Organization. Effective Vaccine Management (EVM) Initiative. Global Data Analysis 2010–2013; 2014. [date accessed: July 3, 2017].
    1. Humphreys G. Vaccination: rattling the supply chain. Bull World Health Org. 2011;89:324–325.
    1. Kaufmann J.R., Miller R., Cheyne J. Vaccine supply chains need to be better funded and strengthened, or lives will be at risk. Health Aff. 2011;30(6):1113–1121.
    1. Zaffran M., Vandelaer J., Kristensen D. The imperative for stronger vaccine supply and logistics systems. Vaccine. 2013;31(Suppl 2):B73–B80.
    1. World Health Organization. WHO; Geneva. Assessing the Programmatic Suitability of Vaccine Candidates for WHO Prequalification; 2012. [date accessed: July 3, 2017].
    1. Naik SP, Zade JK, Sabale RN, Pisal SS, Menon R, Bankar SG, et al. Stability of heat stable, live attenuated Rotavirus vaccine (ROTASIIL®). Vaccine; 2017;35(22):2962–2969. April 20. pii: S0264-410X(17)30499-1. doi: 10.1016/j.vaccine.2017.04.025.
    1. Rid A., Saxena A., Baqui A.H. Placebo use in vaccine trials: recommendations of a WHO expert panel. Vaccine. 2014;32(37):4708.

Source: PubMed

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