Safety and immunogenicity of a typhoid conjugate vaccine among children aged 9 months to 12 years in Malawi: a nested substudy of a double-blind, randomised controlled trial

Nginache Nampota-Nkomba, Osward M Nyirenda, Lameck Khonde, Victoria Mapemba, Maurice Mbewe, John M Ndaferankhande, Harrison Msuku, Clemens Masesa, Theresa Misiri, Felistas Mwakiseghile, Priyanka D Patel, Pratiksha Patel, Ifayet Johnson-Mayo, Marcela F Pasetti, Robert S Heyderman, J Kathleen Tracy, Shrimati Datta, Yuanyuan Liang, Kathleen M Neuzil, Melita A Gordon, Matthew B Laurens, Typhoid Vaccine Acceleration Consortium team, Nginache Nampota-Nkomba, Osward M Nyirenda, Lameck Khonde, Victoria Mapemba, Maurice Mbewe, John M Ndaferankhande, Harrison Msuku, Clemens Masesa, Theresa Misiri, Felistas Mwakiseghile, Priyanka D Patel, Pratiksha Patel, Ifayet Johnson-Mayo, Marcela F Pasetti, Robert S Heyderman, J Kathleen Tracy, Shrimati Datta, Yuanyuan Liang, Kathleen M Neuzil, Melita A Gordon, Matthew B Laurens, Typhoid Vaccine Acceleration Consortium team

Abstract

Background: Typhoid fever is a substantial public health problem in Africa, yet there are few clinical trials of typhoid conjugate vaccine (TCV). We assessed immunogenicity and safety of Typbar TCV in Malawi.

Methods: This substudy was nested within a phase 3, double-blind, parallel design, randomised controlled trial of TCV in children from Ndirande Health Centre in Ndirande township, Blantyre, Malawi. To be eligible, participants had to be aged between 9 months and 12 years with no known immunosuppression or chronic health conditions, including HIV or severe malnutrition; eligible participants were enrolled into three strata of approximately 200 children (9-11 months, 1-5 years, and 6-12 years), randomly assigned (1:1) to receive TCV or control (meningococcal serogroup A conjugate vaccine [MCV-A]) intramuscularly. Serum was collected before vaccination and at 28 days and 730-1035 days after vaccination to measure anti-Vi antibodies by ELISA. Because of COVID-19, day 730 visits were extended up to 1035 days. This nested substudy evaluated reactogenicity, safety, and immunogenicity by age stratum. Safety outcomes, analysed in the intention-to-treat population, included solicited adverse events within 7 days of vaccination (assessed on 3 separate days) and unsolicited adverse events within 28 days of vaccination. This trial is registered with ClinicalTrials.gov, NCT03299426.

Findings: Between Feb 22 and Sept 6, 2018, 664 participants were screened, and 631 participants were enrolled and randomly assigned (320 to the TCV group and 311 to the MCV-A group). 305 participants in the TCV group and 297 participants in the MCV-A group were vaccinated. Among TCV recipients, anti-Vi IgG geometric mean titres increased more than 500 times from 4·2 ELISA units (EU)/mL (95% CI 4·0-4·4) at baseline to 2383·7 EU/mL (2087·2-2722·3) at day 28, then decreased to 48·0 EU/mL (39·9-57·8) at day 730-1035, remaining more than 11 times higher than baseline. Among MCV-A recipients, anti-Vi IgG titres remained unchanged: 4·3 EU/mL (4·0-4·5) at baseline, 4·4 EU/mL (4·0-4·7) on day 28, and 4·6 EU/mL (4·2-5·0) on day 730-1035. TCV and MCV-A recipients had similar solicited local (eight [3%] of 304, 95% CI 1·3-5·1 and three [1%] of 293, 0·4-3·0) and systemic (27 [9%] of 304, 6·2-12·6 and 27 [9%] of 293, 6·4-13·1) reactogenicity. Related unsolicited adverse events occurred similarly in TCV and MCV-A recipients in eight (3%) of 304 (1·3-5·1) and eight (3%) of 293 (1·4-5·3).

Interpretation: This study provides evidence of TCV safety, tolerability, and immunogenicity up to 730-1035 days in Malawian children aged 9 months to 12 years.

Funding: Bill & Melinda Gates Foundation.

Conflict of interest statement

Declaration of interests We declare no competing interests.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure
Figure
CONSORT flow diagram MCV-A=meningococcal serogroup A conjugate vaccine. TCV=typhoid conjugate vaccine. *Five participants had fever within 24 h of eligibility assessment; three participants used anti-pyretics within 4 h of assessment; nine participants had known HIV infection or exposure or other immunosuppressive conditions; three participants received measles–rubella vaccine 1 month before enrolment; one participant received measles-containing vaccine; one participant had an allergy to study or control vaccine; two participants received a systemic immunosuppressant or corticosteroids; one participant had a history of chronic illness; six participants were not included on investigator decision; and two participants did not pass the screening because of malnutrition. †26 participants were excluded from the immunogenicity analysis because had a late day-28 visit. ‡One participant was dually enrolled into the main efficacy study and did not disclose concurrent participation in the safety and immunogenicity study. §Four participants were excluded from the immunogenicity analysis because they had an early day-730–1035 visit.

References

    1. Brockett S, Wolfe MK, Hamot A, Appiah GD, Mintz ED, Lantagne D. Associations among water, sanitation, and hygiene, and food exposures and typhoid fever in case-control studies: a systematic review and meta-analysis. Am J Trop Med Hyg. 2020;103:1020–1031.
    1. Dougan G, Baker S. Salmonella enterica serovar typhi and the pathogenesis of typhoid fever. Annu Rev Microbiol. 2014;68:317–336.
    1. Ajibola O, Mshelia MB, Gulumbe BH, Eze AA. Typhoid fever diagnosis in endemic countries: a clog in the wheel of progress? Medicina. 2018;54:23.
    1. Cruz Espinoza LM, McCreedy E, Holm M, et al. Occurrence of typhoid fever complications and their relation to duration of illness preceding hospitalization: a systematic literature review and meta-analysis. Clin Infect Dis. 2019;69(suppl 6):S435–S448.
    1. Birkhold M, Coulibaly Y, Coulibaly O, et al. Morbidity and mortality of typhoid intestinal perforation among children in sub-Saharan Africa 1995–2019: a scoping review. World J Surg. 2020;44:2892–2902.
    1. Gunn JS, Marshall JM, Baker S, Dongol S, Charles RC, Ryan ET. Salmonella chronic carriage: epidemiology, diagnosis, and gallbladder persistence. Trends Microbiol. 2014;22:648–655.
    1. Feasey NA, Gaskell K, Wong V, et al. Rapid emergence of multidrug resistant, H58-lineage Salmonella typhi in Blantyre, Malawi. PLoS Negl Trop Dis. 2015;9
    1. Klemm EJ, Shakoor S, Page AJ, et al. Emergence of an extensively drug-resistant Salmonella enterica serovar typhi clone harboring a promiscuous plasmid encoding resistance to fluoroquinolones and third-generation cephalosporins. MBio. 2018;9:e00105–e00118.
    1. Global Burden of Disease Collaborative Network Global burden of disease, typhoid fever—level 4 cause. 2020.
    1. Britto C, Pollard AJ, Voysey M, Blohmke CJ. An appraisal of the clinical features of pediatric enteric fever: systematic review and meta-analysis of the age-stratified disease occurrence. Clin Infect Dis. 2017;64:1604–1611.
    1. Meiring JE, Shakya M, Khanam F, et al. Burden of enteric fever at three urban sites in Africa and Asia: a multicentre population-based study. Lancet Glob Health. 2021;9:e1688–e1696.
    1. Barac R, Als D, Radhakrishnan A, Gaffey MF, Bhutta ZA, Barwick M. Implementation of interventions for the control of typhoid fever in low- and middle-income countries. Am J Trop Med Hyg. 2018;99(suppl):79–88.
    1. Khan MI, Franco-Paredes C, Sahastrabuddhe S, Ochiai RL, Mogasale V, Gessner BD. Barriers to typhoid fever vaccine access in endemic countries. Res Rep Trop Med. 2017;8:37–44.
    1. Mohan VK, Varanasi V, Singh A, et al. Safety and immunogenicity of a Vi polysaccharide-tetanus toxoid conjugate vaccine (Typbar-TCV) in healthy infants, children, and adults in typhoid endemic areas: a multicenter, 2-cohort, open-label, double-blind, randomized controlled phase 3 study. Clin Infect Dis. 2015;61:393–402.
    1. WHO Typhoid vaccines: WHO position paper, March 2018: recommendations. Vaccine. 2018;93:13.
    1. The SAGE Working Group on Typhoid Vaccines WS . World Health Organisation; Geneva: 2017. Background paper to SAGE on typhoid vaccine policy recommendations.
    1. Patel PD, Patel P, Liang Y, et al. Safety and efficacy of a typhoid conjugate vaccine in Malawian children. N Engl J Med. 2021;385:1104–1115.
    1. Meiring JE, Laurens MB, Patel P, et al. Typhoid vaccine acceleration consortium Malawi: a phase III, randomized, double-blind, controlled trial of the clinical efficacy of typhoid conjugate vaccine among children in Blantyre, Malawi. Clin Infect Dis. 2019;68(suppl 2):S50–S58.
    1. Cohen BJ, Audet S, Andrews N, Beeler J. Plaque reduction neutralization test for measles antibodies: description of a standardised laboratory method for use in immunogenicity studies of aerosol vaccination. Vaccine. 2007;26:59–66.
    1. Simon JK, Ramirez K, Cuberos L, et al. Mucosal IgA responses in healthy adult volunteers following intranasal spray delivery of a live attenuated measles vaccine. Clin Vaccine Immunol. 2011;18:355–361.
    1. Tapia MD, Sow SO, Medina-Moreno S, et al. A serosurvey to identify the window of vulnerability to wild-type measles among infants in rural Mali. Am J Trop Med Hyg. 2005;73:26–31.
    1. WHO Rubella vaccines: WHO position paper. Recommendations. Vaccine. 2011;29:8767–8768.
    1. WHO Measles vaccines: WHO position paper, April 2017. Recommendations. Vaccine. 2019;37:219–222.
    1. Shakya M, Colin-Jones R, Theiss-Nyland K, et al. Phase 3 efficacy analysis of a typhoid conjugate vaccine trial in Nepal. N Engl J Med. 2019;381:2209–2218.
    1. Qadri F, Khanam F, Liu X, et al. Protection by vaccination of children against typhoid fever with a Vi-tetanus toxoid conjugate vaccine in urban Bangladesh: a cluster-randomised trial. Lancet. 2021;398:675–684.
    1. Sirima SB, Ouedraogo A, Barry N, et al. Safety and immunogenicity of Vi-typhoid conjugate vaccine co-administration with routine 9-month vaccination in Burkina Faso: a randomized controlled phase 2 trial. Int J Infect Dis. 2021;108:465–472.
    1. Mitra M, Shah N, Ghosh A, et al. Efficacy and safety of Vi-tetanus toxoid conjugated typhoid vaccine (PedaTyph™) in Indian children: school based cluster randomized study. Hum Vaccin Immunother. 2016;12:939–945.
    1. Fowlkes A, Witte D, Beeler J, et al. Persistence of vaccine-induced measles antibody beyond age 12 months: a comparison of response to one and two doses of Edmonston-Zagreb measles vaccine among HIV-infected and uninfected children in Malawi. J Infect Dis. 2011;204(suppl 1):S149–S157.
    1. Meiring JE, Gibani M, Ty VACCMG. The Typhoid Vaccine Acceleration Consortium (TyVAC): vaccine effectiveness study designs: accelerating the introduction of typhoid conjugate vaccines and reducing the global burden of enteric fever. Report from a meeting held on 26–27 October 2016, Oxford, UK. Vaccine. 2017;35:5081–5088.
    1. Olaru ID, Mtapuri-Zinyowera S, Feasey N, Ferrand RA, Kranzer K. Typhoid Vi-conjugate vaccine for outbreak control in Zimbabwe. Lancet Infect Dis. 2019;19:930.

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