Diarrhoea continues to be one of the leading causes of death among children worldwide (nearly half a million deaths in the under-fives) and affects children living in low-income countries the most. The main culprit behind childhood diarrhoea is a highly contagious virus called rotavirus.
The introduction of oral rotavirus vaccines for children has significantly reduced diarrhoea caused by the virus, but the vaccines have failed to live up to the promise they showed when tested in clinical trials set in high-income countries.
The reasons why vaccines are less effective in countries where rotavirus is endemic are unclear, but it does highlight the need to develop and test vaccines in countries where the disease is rife, to make sure they work where they are needed.
The goal of an ambitious new research programme, jointly led by Dr Roma Chilengi in Zambia and Professor Nick Grassly at Imperial College London and funded by the MRC, is to develop a human infection study with rotavirus, to help identify better vaccines that protect more children.
New vaccines in the pipeline
There are potentially better vaccines being developed and we urgently need to compare them to the oral vaccines currently offered to children, according to Dr Chilengi.
“The development of rotavirus vaccines that can be injected, such as the ‘trivalent VP8 subunit vaccine’, could potentially offer better protection than oral vaccine administration, because they would overcome challenges faced by live oral vaccines including the negative effects of maternal antibodies in breastmilk, and structural as well functional infant gut mucosa problems induced by malnutrition, persistent disease exposure and co-infections,” he says.
The traditional way to test the effectiveness of new vaccines is through clinical trials, which can be both challenging and expensive to carry out. Controlled human infection studies are increasingly used as a tool to quickly assess promising candidate vaccines to speed up their development, and to improve understanding of infectious disease immunology.
Building upon the HIC-Vac pump-priming project
In 2018, Dr Chilengi was awarded HIC-Vac funding to carry out some preliminary research to lay the foundations for a rotavirus infection study in Zambia.
The interesting aspect of the study is that the team will be using the oral vaccine as a surrogate for natural viral infection to test new vaccines. The oral vaccine is an ‘attenuated’ form of rotavirus – a weakened strain that can’t cause disease but does train the immune system to fight the real virus.
“Thanks to a pump-priming grant from HIC-Vac, we showed that in principle this could work as a model,” says Dr Chilengi.
“We measured how much virus could be detected in babies’ stools by a test called a PCR. Once a baby has been given one dose of the oral vaccine, the amount of virus they shed upon receiving a second dose – a ‘challenge’ – falls because immunity form the first encounter has protected them somewhat.
“We can use this same model to test new vaccines. Instead of giving all the babies the oral vaccine first, some will be given the new injectable vaccine, then followed later by the attenuated oral vaccine as a ‘challenge’. Then we can test their stools for viral shedding to compare and determine if a new vaccine gives better protection.”
From proof of principle to testing new vaccines
After completing the preliminary work to show their idea works, they have been awarded funding from the MRC (just over £775,000) to expand their ambitions and carry out the first controlled human infection study in Zambia.
The study has been carefully designed to minimize any risks involved or discomfort to babies. The PCR tests to measure the virus (as a read out of how well a vaccine works) are carried out on stool samples, so are completely non-invasive.
Any new vaccines will have been rigorously tested for safety; this study is to gauge their effectiveness. The challenge is the licensed oral vaccine – a weakened strain of rotavirus that can’t cause disease – so it’s perfectly safe and does not pose any additional risk to the infants. Plus, because they get a dose of oral vaccine anyway, if a new vaccine isn’t effective, they will still have been immunized just the same as all babies are.
And, of course, the parents of the infants will be given all the information they need about the study and have the final say over whether they are happy for their child to be involved in the research.
Professor Grassly is looking forward to continued partnership with Dr Chilengi in Zambia. “This is an exciting opportunity to see whether the new vaccine – the injectable ‘VP8 subunit vaccine’ – is better than oral immunization. We can also try the two in combination. Even small improvements could save thousands of babies’ lives.”
Beyond the immediate need for better rotavirus vaccines, it’s the first time a controlled human infection study will be carried out in Zambia, and a step towards growing their capacity to develop and test new vaccines.
“Establishing a live attenuated rotavirus human infection challenge model at CIDRZ in Zambia could improve our understanding on why there is a discrepancy between how well vaccines work in clinical trials in endemic versus non-endemic countries,” says Dr Chilengi. “But more importantly, we need to make sure new vaccines work in the right places, for the right people.”
The success of Dr Chilengi and Professor Grassly is testament to the aims of HIC-Vac’s pump-priming funding; it supported the preliminary research needed to set up the study.
Dr Martin Broadstock, Programme Manager for Vaccines, Vector-borne Diseases and Neglected Tropical Diseases at MRC, is pleased to see the project come to fruition. “I am delighted that a HIC-Vac pump-priming award has resulted in this significant funding to Dr Chilengi and Professor Grassly, both of whom engaged with the MRC before their final submission. The ongoing collaboration between CIDRZ and Imperial will benefit many infants worldwide. I look forward to more pump-priming award holders applying to the MRC for further funding.”