Vaccine development requires the conduct of clinical trials to generate the necessary safety, quality and efficacy data needed for licensure1. Starting initially with small trials to demonstrate safety, and progressively scaling up to look at immunogenicity and finally efficacy, this process has resulted in the development of vaccines against 25 diseases, with more in the pipeline2 which have significantly reduced morbidity and mortality since their introduction3.

Vaccine development takes on average 10–15 years and costs at least $500 m to bring a new product to market, with probability of success estimated to be as low as 10%4 The high level of investment of both time and money needed to progress vaccine candidates combined with high risk of failure can disincentivize development of some products. The feasibility of clinical development and the likelihood of regulatory approval are key drivers of developer decision-making when considering which products to progress, especially as vaccines move towards pivotal efficacy studies which require significant investment5. Whilst quality and safety standards are well defined, establishing efficacy can be challenging.

Given that infectious diseases still kill millions of people worldwide, particularly in Africa, some parts of south-east Asia and south America6 alternative strategies must be considered to address the challenges of progressing vaccines through late-stage development.

These challenges can be technical, such as low disease incidence, diagnostic or enrolment challenges, or lack of understanding of protective immunity in target populations. Challenges can also be financial, with candidate vaccines failing to attract the necessary level of investment to conduct efficacy trials if market demand or return on investment are uncertain, falling into “the second valley of death” between late-stage clinical development and licensure7.

The majority of vaccines licenced to date have been assessed for efficacy against clinical disease endpoints in randomised controlled trials (RCT’s), this approach is viewed as the gold standard method to demonstrate the efficacy data required by regulators for licensure. However, this traditional approach is not always feasible in certain situations.

The outbreak of Sudan ebolavirus (SUDV) in Uganda in 2022 highlights this issue for emerging infectious diseases. When the outbreak of SUDV was declared in Uganda8, there were no licenced vaccines, but there were 3 vaccine candidates in development9 Plans were rapidly drawn up by Ugandan authorities and the WHO, to conduct a “ring vaccination” study using WHO’s SOLIDARITY trials core protocol to assess the effect of a single vaccine dose in protecting recent contacts of newly confirmed cases of SUVD against lab-confirmed SUVD10 The first doses of candidate vaccines arrived in Uganda just 79 days after the outbreak was declared. However, before the trial started, the outbreak was declared over. Given the deadly nature of ebolavirus disease (this outbreak recorded 142 confirmed cases and 55 confirmed deaths) medical counter measures to control outbreaks are still urgently needed. Whilst the control and eventual ending of the outbreak was achieved through leadership, teamwork, contact tracing testing and control measures such as quarantines and lockdowns, such measures are not without their significant downsides, particularly for the poorest people in societies where not working means no income to support their families11.

This issue does not only affect emerging infectious diseases, other examples include:

Where disease incidence is low e.g. a cluster-randomised ring vaccination trial for a Nipah virus vaccine was estimated to take 516 years and over 163,000 vaccine doses under current epidemic conditions12.

Where large trials are required e.g. licensure of a maternal GBS vaccine to prevent neonatal disease require enrolment of up to 80,000 pregnant women13,14, or prevention of enteric fever caused by S. paratyphi A, where low attack rates mean efficacy studies would require 100,000–250,000 participants15.

Where unpredictable market demand and return on investment mean products fail to attract necessary investment e.g. new TB vaccines16,17.