Impact case study database

Typhoid fever is a systemic infection caused by Salmonella Typhi, usually through ingestion of contaminated food or water. Between 11,000,000 and 21,000,000 cases and 128,000 to 161,000 typhoid-related deaths occur annually worldwide. While provision of clean water and improved sanitation could control the disease, the engineering works required to do this across low- and middle-income countries cannot be achieved quickly. Vaccines therefore offer early impact on disease while definitive investment in infrastructure is awaited. However, lack of licensed vaccines suitable for administration to children younger than five years had stalled progress towards introduction and there was no investment in the expensive field trials to help build confidence by demonstrating impact. University of Oxford researchers, under the leadership of Pollard, Angus and Basnyat, undertook key research to address this challenge. They then joined a partnership between the University of Maryland School of Medicine and PATH (an international global health non-profit organisation) to aid Gavi (Global Alliance for Vaccines and Immunisation) eligible countries in accelerating introduction of typhoid vaccines for children between 6 months and 15 years old.

The new typhoid conjugate vaccines had the potential to overcome many of the challenges that impeded uptake of earlier vaccines, including longer-lasting protection, fewer doses, and suitability for children younger than two years of age, allowing for inclusion in routine childhood immunisation programmes. However, they needed to be tested in a safe and ethical way. Conducting human challenge studies, where volunteers received an infection with a live pathogen, required the team to overcome many challenges to meet modern manufacturing, regulatory, safety and ethical standards. The development of the human challenge model of typhoid infection informed the WHO guidelines on development of new typhoid conjugate vaccines, and was prioritised by the 64th meeting of the WHO Expert Committee on Biological Standardization, 21-25 October 2013 [A]. These guidelines were made available for all manufacturers developing new vaccines for the disease.

The efficacy data on the new typhoid conjugate vaccine Typbar-TCV from the human challenge study conducted by the University of Oxford in 2016 proving a protective efficacy of 54%-87% against typhoid [3], were requested by the WHO as evidence in the prequalification of Typbar-TCV. Prequalification enabled procurement by UNICEF, Pan-American Health Organisation and Gavi. The WHO’s SAGE recommendations and the prequalification of Typbar-TCV directly supported the decision by Gavi to release USD85,000,000 to support countries roll out typhoid vaccine, announced in early 2018 [B].

Learning that an approach is unlikely to be effective is important as it avoids wasted resources. Observations on the role of typhoid toxin in invasion study [2] following development of the human challenge model [1] halted further development of therapeutic monoclonal antibodies using typhoid toxin as a target and experimental vaccines based on the toxin.

Having established the human challenge model, Pollard then took the opportunity to use these volunteers’ donated blood to develop a serum standard for typhoid conjugate vaccines [6], which was approved by WHOs Expert Committee on Biological Standardisation (ECBS) for all manufacturers developing typhoid conjugate vaccines [C]. This is a biological reference material vital for international standardisation of vaccine development comparisons and immunogenicity studies. As of 14 December 2020, the NIBSC have sold 232 vials of the standard.

Field trial participants: Field trials of the Typbar-TCV were conducted in Malawi (28,000 children), Bangladesh (32,500 children) and Nepal (20,000 children). In August 2018, interim study results from the 20,000 participants aged 9 months to 15 years vaccinated in Nepal demonstrated an efficacy rate of 82% [5], and thus it can be estimated from the data that in a trial population of 80,000 vaccinated children, this should result in a reduction of 200 cases of typhoid fever per year.

Mass adoption: 2018 was the first year in which countries could apply for Gavi support for purchase and delivery of typhoid vaccines for children between 6 months and 15 years old, with the first routine immunisations taking place in 2019 [D]. Zimbabwe carried out a Gavi-funded mass Typbar-TCV vaccination campaign between February and March 2019 that targeted 318,000 children in communities affected by an ongoing typhoid outbreak in Harare [E]. A two-week vaccination campaign, targeting 10,000,000 children of 9 months to 15 years old in urban areas of the Sindh province in Pakistan with Typbar-TCV, took place in late 2019 [F], the beginning of Pakistan’s introduction of the vaccine into their routine immunisation programme.

Routine immunisation: Though previously thought to be at low risk of typhoid, when it was discovered that under 3 year olds were at risk, there were concerns about how to best protect them, specifically as this age group respond less well to the previous vaccines and more to the newer conjugate vaccines. This age group is difficult to study as testing vaccines for young children requires prior testing in adults. Developing a way to test the conjugate vaccine for efficacy quickly, using the human typhoid challenge model [1, 3] was a crucial step. Following on from Pakistan’s introduction of the vaccine in to their routine immunisation programme at the end of 2019, Liberia and Zimbabwe also approved the introduction of TCV into their routine childhood immunisation programmes (implementation was due to take place in 2020 but was delayed to 2021 due to COVID) [F].

Vaccine rollout was given additional impetus due to the increasing problem of antimicrobial resistance, meaning in some areas typhoid had become untreatable with antibiotics. This was particularly a problem in the Sindh province of Pakistan where the Pakistan Health Authorities documented the outbreak of typhoid fever cases citing 5,274 cases of extremely drug resistant typhoid of a total of 8,188 typhoid fever cases (2016 - 2018). The vaccine efficacy data [3], amongst other University of Oxford research, is cited in the WHO position and background papers on the use of typhoid vaccines to combat resistance [Gi]. Following presentation of the interim field trial results in Nepal [5], the administration of Typbar-TCV to 10,000,000 children (detailed above) in Pakistan was approved on an emergency basis in 2019. The vaccine was specifically used here to contain the disease, due to widespread antimicrobial resistance of S. Typhi against ceftriaxone [H], one of the most commonly used antibiotics against typhoid fever. The impact of this effective vaccine in the control of antimicrobial resistance has been shown to be crucial, as already evidenced by the number of cases halving in areas of Pakistan following vaccination [I] (formal evidence from Pakistan delayed publishing due to COVID).

Vaccine efficacy and safety data generated in the human challenge model were used to support the 2018 WHO Strategic Advisory Group of Experts on Immunisation (SAGE) global policy recommendations for TCVs [Gi]. The policy references utilising the human challenge model ([3] and two additional University of Oxford publications), in the section on Immunogenicity, efficacy and effectiveness of the TCV. This policy recommended that the vaccine is used in all high burden areas from 9 months to 15 years of age. University of Oxford research is extensively referenced in the background papers [Gii] and guidance [1, 3 and three additional University of Oxford publications] as it provided the only efficacy data available at the time the recommendations were made. Furthermore, the safety data from Oxford-led field trials in Nepal [5] were referenced in WHO Global Advisory Committee on Vaccine Safety’s review of typhoid vaccines [J].

Age-stratified data on clinical and sub-clinical disease burden is important for countries to decide whether to prioritise vaccine introduction. Pollard led large-scale studies of the burden of typhoid in Bangladesh, Malawi and Nepal to inform the respective Governments on the priority of typhoid control [4]. For example, Pollard has been working in Nepal with Gavi and PATH [Ki] and has engaged with the Nepal Government to support introduction of TCV in Nepal’s routine immunisation. Following discussion of the surveillance study [4] and human challenge model data [2], in 2017 the National Committee on Immunization Practices recommended “ the need for typhoid vaccine studies to be conducted in Nepal, and in the view of the huge burden of disease, Nepal should be an early adopter of typhoid conjugate vaccine once funding is available” [Kii].