In a paper published in The Lancet Infectious Diseases in April 2023, researchers detailed the results of a Phase I trial for a ChAdOx1 vaccine against Rift Valley fever. The paper suggests that the vaccine proved “safe, well tolerated, and immunogenic” in a single dose in the study population. The authors state that Rift Valley fever vaccine development has been identified as an urgent priority by the WHO and the African Union due to its potential to “cause a public health emergency with severe health consequences and major economic impacts”.
Although there are two candidate vaccines, one of which is “currently recruiting” for a Phase II trial, this study evaluates the use of the ChAdOx1 platform. This is deployed for use against COVID-19 in “more than 180 countries”, but the study is the “first clinical evaluation of its use for Rift Valley fever in humans”.
Rift Valley fever
Rift Valley fever was identified by WHO as a priority pathogen in July 2022. It is a mosquito-borne viral zoonosis that primarily affects domestic livestock and humans in Africa and the Middle East. First identified in Kenya in 1930, it is “characterised by high rates of death (>90%)” in young animals and animal pregnancy loss. Although mosquito transmission does occur, spillover has most commonly been associated with “direct contact with infected animal tissues”.
Human manifestations of the disease “can vary widely”. However, most people experience a “self-limiting febrile illness”. An estimated 0.5%-3% of patients develop “severe symptoms” such as haemorrhagic diatheses. In these cases, fatality can be as high as 50%. Further complications, such as meningoencephalitis and ocular pathology, can result in “debilitating sequalae”.
The vaccination landscape
Although there are licensed livestock vaccines, none are available for human use. Due to the demonstrated importance of neutralising antibodies in protection, the “aim” of Rift Valley vaccinology has been to “design vaccines that are safe and highly immunogenic for protective neutralising antibodies, alongside other WHO optimal product characteristics.
The target population for a human Rift Valley fever vaccine is people who live in areas prone to outbreaks, particularly those in contact with livestock. Although the authors recognise the “importance of livestock vaccination” for a reduction of animal loss but also limitation of virus transmission to humans, it “does not obviate the need for a human vaccine”.
“Routine livestock vaccination will rarely approach 100% compliance, human cases have been reported in the absence of livestock outbreaks, and there is a potential for epidemic spread.”
Two vaccine candidates have already been evaluated in humans. However, the first, an inactivated vaccine, did not demonstrate seroconversion in participants. The second is a live-attenuated vaccine, which was investigated in humans but has since seemed to shift for use as a veterinary vaccine.
“Since 2012, a One Health approach to Rift Valley fever vaccinology has been taken by developing a single vaccine, ChAdOx1 RVF, for use in both humans and livestock.”
ChAdOx1 RVF
The vaccine comprises the ChAdOx1 adenovirus vector expressing a codonoptimised transgene for the Rift Valley fever (RVF) viral Gn and Gc glycoproteins. It uses the same platform used for the ChAdOx1 nCoV-19 COVID-19 vaccine. It has shown “remarkable safety, immunogenicity, and 100% efficacy” against wild-type Rift Valley fever virus challenge in livestock in Kenya.
This study aimed to evaluate the vaccine’s safety, tolerability, and immunogenicity in a first-in-human Phase I trial of healthy adults in the UK. It was a dose-escalation, open-label, non-randomised clinical trial, taking place at the Centre for Clinical Vaccinology and Tropical Medicine in Oxford. The researchers recruited local healthy adult volunteers between the ages of 18 and 50 years.
The vaccine met “many of the optimal product characteristics listed in the WHO target product profile”. For example, a favourable safety profile, rapid onset of neutralising antibodies, and cellular immunity within 2 weeks of a single-dose vaccination were observed.
The vaccine also holds “relatively easy” deployment potential, the authors suggest. It has inherent thermostability, which allows fridge storage for at least a year, and a scalable manufacturing process for these ChAdOx1- vectored vaccines has been developed and “successfully” used for the COVID-19 vaccine.
Potential for concern
The authors recognise the “legitimate concern” that, as a “large proportion of the world’s population” has received the ChAdOx1 nCoV-19 vaccine, multiple doses of homologous viral vectors could be problematic due to a “build-up of antivector immunity”. However, evidence from previous vaccine trials indicates “neither previous doses of ChAdOx1 vaccines or naturally acquired anti-ChAdOx1-vector neutralising antibodies lead to impaired immune responses to the encoded antigen”.
Future investigations
Due to the short follow-up duration of this study, the authors recommend further trials to assess any rare adverse effects and to establish “long-term durability of the immune response”. They also acknowledge that in this study, the participants were “predominantly White and from a population in which Rift Valley fever is not endemic”. Thus, this and other candidate human Rift Valley fever vaccines “require evaluation in regions endemic for Rift Valley fever.
To access the study in full, click here.
