An inexpensive malaria vaccine that can be produced on a massive scale has been recommended for use by the World Health Organization (WHO), with agreements already in place to manufacture more than 100m doses a year, writes MedicalBrief. It has 75% efficacy and is less than half the cost of the first such vaccine, developed two years ago, and is easier to produce at volume.
It has taken more than a century of scientific effort to develop effective vaccines against malaria, and the new one, developed by the University of Oxford, is only the second ever to have been developed.
It is almost two years to the day since the first vaccine – called RTS,S and developed by GSK – was backed by the WHO, reports BBC News.
RTS,S or Mosquirix, was recommended for use in 2021 and has already been given to 1.8m children in Ghana, Malawi, and Kenya. Doses are expected to arrive in nine more countries in Africa by the end of the year.
But the 18m doses of that vaccine that are expected to be available between now and 2025 “are only about 10% of what we need” to protect the estimated 40m children born every year in malaria-affected areas”, said Matthew Laurens, a malaria vaccine expert at the University of Maryland School of Medicine.
The WHO said the effectiveness of the two vaccines was “very similar” and there was no evidence one was better than the other.
However, the key difference is the ability to manufacture the University of Oxford vaccine – called R21/MatrixM – at scale.
The world’s largest vaccine manufacturer, the Serum Institute of India, is already lined up to make more than 100m doses a year, with plans to scale this up to 200m per annum.
The WHO said the R21 vaccine would be a “vital additional tool”. Each dose costs $2-$4, and four doses are needed per person. That is about half the price of RTS,S.
The two vaccines use similar technologies and target the same stage of the malaria parasite’s lifecycle. However, R21 is easier to manufacture as it requires a smaller dose and uses a simpler adjuvant (a chemical given in the vaccine that jolts the immune system into action).
In 2021, there were 247m cases of malaria and 619 000 people died, most of them children under five. More than 95% of malaria is found in Africa.
Life-saving potential
Dr Matshidiso Moeti, the WHO regional director for Africa, said: “Delivered to scale and rolled out widely, the two vaccines can help bolster malaria prevention, control efforts and save hundreds of thousands of young lives.”
Data from a trial involving 4 800 children in four African countries suggest R21 is 75% effective at preventing the disease in areas where malaria is seasonal.
The WHO’s strategic advisory group of experts said that figure was comparable to RTS,S in seasonal areas.
The phase 3 R21 trial included children between the ages of five months and 36 months at sites in Mali, Burkina Faso, Kenya, and Tanzania, reports the journal Science.
Most were given prophylactic treatment with antimalarial drugs, also known as seasonal malaria chemoprevention (SMC), which is now standard in many malaria-affected regions.
Children then received either R21 or a rabies vaccine as a control.
Last year the team reported preliminary results suggesting the vaccine’s efficacy was above 70%. The Lancet preprint now reports that at the three trial sites where malaria transmission is seasonal, the vaccine had 75% efficacy over 18 months compared with preventive drugs alone.
At the two sites with year-round transmission, the efficacy was 68%.
That’s slightly higher than recent trial results for RTS,S, which found an efficacy over three to five years of 58% compared with anti-malaria drugs alone.
But Laurens noted that the two vaccines were tested in different settings and under different conditions. The reported background levels of malaria, for example, “suggest that R21 may have been tested at sites with less intense malaria transmission versus RTS,S phase 3 sites”, he said, which may have boosted R21’s efficacy numbers.
The R21 efficacy was slightly higher in children who received their vaccines early, between the ages of five months and 17 months.
That could be a sign that the vaccine is less effective in people who have already been exposed to malaria, Laurens speculated.
If so, R21 might have lower efficacy in areas with very high malaria incidence, where young infants are exposed at an early age, he added.
As with RTS,S, researchers also worry protection will wane. For RTS,S it dropped from 56% after one year to just 36% after three years.
However, yearly boosters restore protection, especially when combined with antimalarial drugs, noted Alassane Dicko, a malaria expert at the University of Sciences, Techniques and Technologies of Bamako, who helped lead the R21 trial centres in Mali and has also helped lead trials of RTS,S.
In the R21 trial, children received three doses four weeks apart and a booster dose roughly 12 months after the third dose. Ongoing trials are testing the efficacy of further R21 boosters. Dicko said, however, that there are some indications a booster every two years might be sufficient, a prospect the team is testing in an extension of the trial.
The trial has found few significant side effects so far. Five children who received R21 and one child in the control group suffered fever-related seizures within two days of vaccination, which the researchers deemed was probably due to vaccination.
However, said Laurens, the study is too small to pick up rare side effects. “Everything looks good so far,” he added, but it will be important to continue careful surveillance.
Nigeria, Ghana, and Burkina Faso have already approved R21 for use based on earlier data, but at least 28 countries in Africa plan to introduce a WHO-recommended malaria vaccine as part of their national immunisation programmes.
Gavi, the Vaccine Alliance, has approved providing support to roll out malaria vaccines to 18 countries, The Guardian reports.
The RTS,S vaccine will be available in some African countries in early 2024 and the R21 malaria vaccine is expected to become available in mid-2024, according to the WHO.
Observers have heralded the announcement of R21, but warned the vaccine was “no magic bullet” in the fight against malaria and that it should be used in tandem with other measures, such as insecticide-treated nets and indoor spraying to prevent the disease.
Dr Michael Charles, chief executive of the RBM Partnership to End Malaria, said the announcement was “a step in the right direction” but that there were still “major hurdles to overcome”.
“In the face of significant funding shortfalls and the growing threats of insecticide and drug resistance, and climate change, further investment must be urgently mobilised to scale up, manufacture and roll out malaria vaccines to ensure they are readily accessible to countries that decide to use them,” he said.
Gareth Jenkins, from Malaria No More UK, said: “The reality is that malaria financing globally is far from where it needs to be. Annual deaths from malaria rose during the pandemic and are still above pre-pandemic levels, so we cannot afford to be complacent as new tools are developed.”
Study details (Preprint)
A Phase III Randomised Controlled Trial Evaluating the Malaria Vaccine Candidate R21/Matrix-M™ in African Children
Mehreen Datoo, Alassane Dicko, Halidou Tinto, et al.
Posted in The Lancet on 26 September 2023
Abstract
Background
Developing malaria vaccines has proved difficult with many challenges, including polymorphic antigens, modest field-trial efficacy, and now limitations on vaccine supply preventing widespread impact. RTS,S/AS01, the most effective malaria vaccine candidate to date, demonstrated 56% efficacy against uncomplicated clinical malaria over 12 months in a licensure trial in African children. Recently, we found that a new R21 nanoparticle in the saponin adjuvant Matrix-M™ showed over 75% efficacy against a similar endpoint with seasonal administration in a phase IIb trial in Burkina Faso.
Methods
We report the results of a phase III trial of the R21/Matrix-M™ malaria vaccine in 4800 children across five sites in four African countries with differing malaria transmission intensities and seasonality. Children aged 5-36 months were included at all sites. Participants were randomised 2:1 to receive a 5µg dose of R21 in 50µg Matrix-M™ adjuvant or a control vaccine (licensed rabies vaccine). Vaccines were administered as three doses, four weeks apart, with a booster 12 months following the third dose. Half the children recruited were vaccinated at two sites with seasonal malaria transmission and the remainder at “standard” sites with perennial malaria transmission using year-round age-based immunisation. Evaluation of 12-month vaccine efficacy (VE) against clinical malaria was the primary endpoint. VE against multiple malaria episodes and severe malaria as well as safety and immunogenicity were also assessed. We report follow-up to 18 months at seasonal sites and 12 months at standard sites.
Findings
The vaccine was well tolerated with injection site pain and fever as the most frequent local and systemic adverse events. A non-significant trend towards more febrile convulsions was observed in those who received R21/Matrix-M™ compared with rabies vaccines. There was no significant difference in the number of Adverse Events of Special Interest (AESIs) and Serious Adverse Events (SAEs) between the vaccine groups. Overall, 12 months VE was 75% (95% CI 71-79; p<0.001) at the seasonal sites and 68% (61-74; p<0.001) at the standard sites for time to first clinical malaria episode. VE against multiple clinical malaria episodes was similar: 75% (71-78; p<0.001) at the seasonal sites and 67% (59-73; p<0.001) at the standard sites. There was similar waning of efficacy over the first year of follow-up at both seasonal and standard sites. At the seasonal sites, a booster dose maintained efficacy to 18 months at the seasonal sites: VE was 74% (70-77; p<0.001) for time to first clinical malaria episode and 72% (68-75; p<0.001) against multiple clinical malaria episodes. Vaccine-induced antibodies against the conserved central NANP repeat sequence of the circumsporozoite protein correlated strongly with vaccine efficacy. Higher antibody titres were observed in the 5–17-month age group compared with 18–36-month-olds (p<0.0001). When compared with the older age group, the younger age group, in whom this vaccine is most likely to be deployed first, showed the highest 12-month vaccine efficacy on time to first clinical malaria episode at both seasonal, 79% (73-84, p<0.001), and standard sites, 75% (65-83, p<0.001).
Interpretation
R21/Matrix-M™ has a well-tolerated safety profile and offers high-level efficacy against clinical malaria in African children at sites of both seasonal and perennial transmission. This low-cost vaccine, soon to be available at a scale of over 100m doses a year, and already licensed in three African countries (Burkina Faso, Ghana & Nigeria), could make a substantial contribution to reducing the burden of malaria disease and deaths in sub-Saharan Africa.
BBC News article – Malaria vaccine big advance against major child killer (Open access)
The Guardian article – Cheaper, more effective malaria vaccine wins WHO approval (Open access)
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