Typhoid conjugate vaccines: making vaccine history in Africa

KEYWORDS:

• Typhoid
• Africa
• conjugate vaccines
• antimicrobial resistance
• epidemiology
• history
• GAVI
• WHO
• Salmonella

1. Introduction

The 21 February 2018 was a day in vaccine history as 4-year old Golden Kondowe became the first child in Africa to be enrolled in an individually randomized vaccine efficacy trial of a newly WHO pre-qualified typhoid conjugate vaccine (TCV) in Blantyre, Malawi.

Typhoid fever, a systemic illness characterized by prolonged fever following the ingestion and subsequent invasion of the pathogen Salmonella enterica serovar Typhi (S. Typhi), has been reported from the African continent for over 100 years [1]. Known to predominate in populations with poor drinking water quality and inadequate sanitation, disease incidence has remained a public health problem for many African countries [2]. Recent and repeated introductions of multidrug resistant (MDR) S. Typhi from Asia into East and Southern Africa have resulted in widespread and prolonged epidemics in many urban centers on the continent [3,4]. With increasing urbanization applying further pressure on already fragile infrastructure, and the real threat of increasing antimicrobial resistance (AMR) to fluoroquinolones or third-generation cephalosporins emerging in Asia, the situation for Africa could yet become much worse [5].

However, the recent WHO pre-qualification of the TCV Typbar-TCV® [6] following promising vaccine efficacy results from the Oxford typhoid controlled human infection model (CHIM) [7] provides hope that there is now a vaccine which may have impact on global typhoid burden.

2. Epidemiology

Data from which to estimate typhoid burden in Africa are limited to only a few population-based studies from within the continent. A systematic review including seven studies estimated a total number of 3,090,395 cases in Africa per year with 33,490 deaths [2]. Since this publication, the Typhoid Surveillance in Africa Program (TSAP), a large multisite study, performed surveillance across 10 countries, in 13 sites, with incidence estimates ranging from 0 up to 383 cases per 100,000 person-years observation [8]. What is very clear is the significant spatial and temporal heterogeneity of typhoid burden in Africa. There has been a well-documented increase in cases throughout East and Central/Southern Africa following multiple introductions of the H58 MDR strain from the Indian subcontinent, and there have been well-described local epidemics and outbreaks with this clade [4,9–12] while different non-H58 MDR clades have been shown to circulate in West Africa [13]. The distribution of cases between urban and rural sites is currently unclear and represents a major data gap.

Following the increase in case numbers witnessed after the introduction of MDR S. Typhi, there is concern over the current extensively drug-resistant (XDR) outbreak in Pakistan [5]. Within many resource-poor African countries, access to the necessary antibiotics is limited and they are more costly. The scenario of untreatable typhoid infection is foreseeable making the Strategic Advisory Group of Experts (SAGE) recommendation of vaccine introduction to countries with high AMR both timely and relevant [14]. Indeed, this may be the first vaccine where AMR is acting as a predominant motivation for introduction.

Improvements in both drinking water quality and sanitation have been successful in reducing the rates of disease in many developed countries, but interventions on this scale for much of Africa would require a long timescale and large investment, underlining again the importance of vaccination for more immediate control and reduction of disease.

Unlike in Asia, Salmonella enterica serovar Paratyphi (S. Paratyphi), the other major cause of enteric fever, has not been demonstrated to cause a large disease burden in Africa. Currently, there is no licensed vaccine for S. Paratyphi although some are in development.

3. Typhoid vaccines

Two typhoid vaccine trials have previously been conducted in Africa. The first in Alexandria, Egypt, using the live, oral Ty21a vaccine demonstrating a statistically significant reduction in typhoid fever cases in the vaccine arm with 0 blood culture-confirmed cases compared to the placebo arm with seven cases following 1 year of surveillance in children aged 6–7 years [15]. The second in the Transvaal region of South Africa using a Vi-capsular polysaccharide (Vi-PS) vaccine demonstrated a protective efficacy of 64% in children aged 5–15 years after 21 months of surveillance [16]. Similar results were replicated in field trials in Asia, and both the Vi-PS and Ty21a vaccines received WHO recommendation in 2008 for programmatic use in countries with high burden [17]. However, due to the relatively low efficacy demonstrated particularly for younger children due to the T-cell-independent nature of the polysaccharide vaccine, the scarcity of data on burden of disease, and the impending arrival of more efficacious conjugate vaccines, GAVI funding was delayed.

The Tybar-TCV vaccine developed by Bharat Biotech International, Hyderabad, India, consists of 25 μg of Vi polysaccharide conjugated to a nontoxic tetanus toxoid protein carrier. Conjugation induces a T-cell-dependent response with improved immunogenic properties allowing administration in early infancy [18]. Immunogenicity data from a phase 3 study of the Tybar-TCV performed in India demonstrated consistently higher anti-Vi IgG responses than the Vi-polysaccharide control (anti-Vi IgG 1292 to 1937 EU/ml Typbar-TCV® vs. 411 EU/ml Typbar Vi). The vaccine was noted to be immunogenic in children under 2 years of age, and long-term persistence of anti-Vi has been demonstrated from 3 to 5 years postvaccination [19].

Recent data from the Oxford typhoid CHIM, where healthy volunteers received Tybar-TCV, Vi-PS, or control vaccine and then 1 month later received oral challenge with live typhoid bacteria, demonstrated a protective efficacy of 87.1% when a clinical end point of fever >38°C for >12 h followed by positive blood culture was used [7]. Both the immunogenicity and CHIM efficacy data were important in securing WHO pre-qualification.

With evidence of immunogenicity and now efficacy within the constraints of CHIM, what is now required for policy makers and individual governments are field trials to demonstrate the degree of clinical impact alongside cost-effectiveness data to demonstrate the economic benefit that countries could expect to see through the introduction of this vaccine.

Cost-effectiveness analyses from modeling data suggest that TCV introduction would be cost-effective, and even cost-saving in certain epidemiological contexts, with the largest impact demonstrated by combining routine vaccination with a catch-up campaign of older age groups [20].

4. Further evidence being generated

Building on the recently published TSAP program, the Bill and Melinda Gates Foundation (BMGF)-funded Severe Typhoid Fever Surveillance in Africa (SETA) program is conducting further epidemiological research investigating the incidence and nature of severe typhoid disease across six different sites in Africa [21]. With joint funding from the BMGF and the Wellcome Trust, the Strategic Typhoid alliance across Africa and Asia (STRATAA) study is conducting a comprehensive program of research to further understand the burden of enteric fever with sites in Africa and Asia, aiming to improve the understanding of incidence, transmission, AMR, and diagnostics for typhoid in different epidemiological settings [22].

With $36.9 million funding from BMGF, TyVAC has brought together key partners from the University of Maryland Centre for Vaccine Development, the University of Oxford’s Oxford Vaccine Group, and PATH to accelerate the introduction of TCVs into areas of the world. In Blantyre, Malawi, building on an already well-established typhoid surveillance system at the Malawi Liverpool Wellcome Trust Clinical Research Programme [22], an individually randomized, double-blind, controlled trial recruiting 24,000 children aged 9 months to 12 years comparing the protective efficacy of Tybar-TCV to Meningococcal A vaccine has begun. With effective engagement of local communities, ministries of health and education, and community leaders, a school-based vaccine campaign is under way aiming to vaccinate the total number of children in less than 6 months with a period of passive blood culture surveillance for confirmed S. Typhi bacteremia for up to 3 years.

The primary outcome for the trial is to determine the efficacy of Typbar-TCV in reducing the rates of symptomatic, blood culture-confirmed S. Typhi infections among vaccinated children compared to control. There are a number of secondary outcomes related to the safety and immunogenicity of the vaccine within a subset of participants. Alongside this, there are a number of exploratory, non-etiologic outcomes measuring the impact of vaccine against things such as all fever presentation to health-care facilities, antibiotic usage, blood culture collection, and severe complications and mortality. A separate trial is being run in parallel to estimate the economic impact of typhoid on both the individual and institutional level to provide cost of illness and cost-effectiveness data.

5. GAVI, the vaccine alliance

In November 2017, GAVI approved US$85 million worth of funding for the 2019–2020 window to support eligible countries to introduce TCVs [23]. Considering 36 of the 47 GAVI-eligible countries are within Africa, this presents a huge opportunity for the continent. Looking at recent introductions of new vaccines into the continent, rotavirus and pneumococcal conjugate vaccines have been introduced into 29 and 33 different GAVI-eligible African countries, respectively, often ahead of schedule and demonstrating significant impact on disease burden [24–26].

6. Conclusion

With robust evidence of the high incidence of infection across many African countries, pre-qualification of a safe and efficacious vaccine demonstrated through CHIM, applicable field trials underway collecting the efficacy and economic evidence individual countries require, and the commitment of funding bodies to introduce, Golden Kondowe may prove to be the first of millions of children within Africa to receive and be protected by this vaccine, reducing the burden of typhoid, protecting against growing AMR, and improving the lives of many across the continent.

Declaration of interest

J Meiring was funded by the Wellcome Trust Strategic Award No. 106158/Z/14/Z. M Gordon was funded by the Strategic Typhoid Alliance across Africa and Asia funding Wellcome Trust Strategic Award No. No. 106158/Z/14/Z and the Bill and Melinda Gates Foundation No. OPP1141321. Typhoid Vaccine Acceleration Consortium Funding from Bill and Melinda Gates Foundation No OPP1151153. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The manuscript was not funded.