RTS,S is a vaccine that promises to reduce severe malaria by 30% in fully vaccinated children. A research team estimates that the vaccine could prevent 3-10 million cases of severe malaria each year and save the lives 14,000- 51,000 children depending on how it is implemented.
However, these plaudits failed to mention that the key ingredient in the revolutionary vaccine was almost 35 years old and that scientists have known since late 1990s that it was likely somewhat effective in protecting against malaria.
The delay in the arrival of a vaccine against malaria, at a time when Covid-19 vaccines could be developed and approved in less than a year, raises questions. Researchers involved in the development and approval of RTS.S believe the reason lies in the difficulties of creating a vaccine against this vexing parasite. They also point out the lack of funding and urgency behind malaria research. This impeded the flow of trials.
Ashley Birkett, director at PATH’s malaria vaccine initiative, said that the people affected by malaria are not Europeans or Australians. They are children from poor African countries. “Unfortunately, I believe we must accept that this is part of why there has been so much neglect in the community.”
Since the 1960s, researchers have been looking for a vaccine against malaria. They discovered a protein found on the parasite’s skin, known as circumsporozoite proteins, in 1980 and realized that a vaccine against this protein could give immunity. The military requested that they develop a vaccine against malaria to protect their troops abroad after U.S. government researchers had sequenced the gene in 1984. The government then asked Smith, Kline & French, a predecessor company to GlaxoSmithKline, for assistance.
Experts said the work was difficult. Experts noted that the malaria parasite’s life cycle is complex. It can go through at least three stages once it has entered humans. A vaccine that is developed to combat a specific stage of the disease must be effective. It will not work if the parasite moves on to the next stage. It is not possible to use the basic tools available today to accelerate vaccine development.
There were more than a dozen vaccines that failed to work based on circumsporozoite proteins. RTS,S was the exception. The RTS,S exception was made in the late 1980s and early 90s when the team developed technical details. A 1998 Gambia trial, which involved 250 men, showed that the vaccine had prevented 34% of all infections.
Brian Greenwood, an infectious diseases expert at the London School of Hygiene and Tropical Medicine, who participated in the Gambia trial, said, “That was really what the start of RTS.S.”
Greenwood said that attention to the vaccine was driven more by intellectual curiosity than a sense medical urgency, at least for the wider public and not just the American military. “I don’t believe there was any kind of push. He said that it was done by more academics who were interested in immunology. It wasn’t a public health problem.
Undark was told by people involved in vaccine development that the promising shot was about face a new set of challenges: the many tribulations that can come with testing a vaccine without a commercial market.
Ripley Ballou was a vaccinologist and then worked at Walter Reed Army Institute of Research. He flew to Europe in 1999 to meet with GSK executives. He recalled that he was still in the Army at that time and that he and his GSK colleagues were present in a conference room with long tables to discuss their findings from the Gambia trial. He said, “We had this glimmering of hope that came out of this study that said, ‘you know what, something’ and that we think it was time to take it to a next step.” The next step would be to test the vaccine in children, the group that would be most affected.
GSK was willing to move forward, provided that Ballou and his team could raise additional funds from a partner organisation. GSK was at high risk of the project failing. Even if it succeeded, GSK would not receive any financial rewards. The U.S. military wasn’t interested in RTS.S because it was not convinced that its effectiveness would be sufficient to protect troops.
The Malaria Vaccine Initiative at PATH, which was established in 2011 through a grant from Bill and Melinda Gates Foundation, funded the work instead.
The vaccine manufacturers soon realized that testing the vaccine in Africa was not an easy task as they began to launch trials. Ballou said that there were many logistical problems. He recalled that he had to travel to find a building without any interior, just a concrete shell. Then, he said, “We had the task of turning it into a laboratory.” That took time and money.
These trials were also intended for young infants and small kids. Therefore, the Phase I and 2 trials, which looked at the shot’s safety, efficacy and safety, were first performed in adults and then in older children. Finally, the Phase III and IV trials were conducted in small children to optimize the dose against side effects for each age. Greenwood stated that the entire process took approximately 10 years.
Phase II trials showed promising results, with infants experiencing a 65.9% reduction in infection rate compared to the control group within the first three months. This led to a Phase III trial that was not initiated until 2009. The trial design was difficult. Ballou stated that “Nobody had ever done an malaria vaccine trial at such a scale.”
Phase III trials were conducted in seven sub-Saharan African nations from 2009 to 2014. Over 15,000 children were enrolled. The results were encouraging, so GSK started preparing a manufacturing plant for the shot according to Schuerman.
A WHO review of Phase III trial data from October 2015 revealed that meningitis rates were higher in the vaccine-vaccinated group than in the control, and that deaths were higher among girls who had been vaccinated, though it wasn’t known if this was due to the shot. The WHO requested a larger trial to address these concerns and test the vaccine in a wider real-life setting. Multiple scientists said that the announcement was sudden. Schuerman stated that the manufacturing side had to be shut down. He said that instead, once more, the vaccine team was responsible for setting up clinical trials. This included funding, selecting countries to implement the trial, and hiring personnel.
Most researchers today agree that additional research was necessary. “Given the global attitude to vaccines, it was important that we ruled out potential safety issues,” stated Wongani Nyangulu (a Southern Malawian physician) who is leading a phase IV research site.
The trial was launched after a four-year process. The vaccine was eventually given to 900,000 children in Ghana and Malawi. The WHO reviewed the results and recommended that the vaccine be widely used in areas with moderate to high levels of malaria transmission by October 2021. GAVI, the international agency that distributes and funds vaccines in poor countries announced in December that it would invest $155.7 Million in an RTS/S rollout.
RTS,S was available for widespread use more than 20 years after its first promising trials.
RTS.S approval was less than two years after the virus’s emergence. By that time, Covid-19 vaccines had been approved and developed around the globe.
Researchers in sub-Saharan Africa have been frustrated by these apparent disparities. In an essay written for SciDev.Net last august, Damaris Matoke Muhia, a scientist from the Kenya Medical Research Institute, stated that if the same amount of energy and resources was directed to malaria vaccine development, then malaria could be eradicated. (She noted that malaria was killing more people than Covid-19 at the time.
The discrepancy was also noticed by other African researchers. Deus Ishengoma is a Tanzanian malaria expert and he noted that the speed of the Covid-19 vaccine development meant there would never be an excuse for not developing a vaccine for malaria within the next 10 years.
Others cautioned that comparing vaccines is not fair. Birkett, the executive at PATH, stated that Covid is an easier target for vaccines. He said that malaria was a much more difficult target for a vaccine than Covid. Experts also believe RTS,S may have slowed the process. Birkett said that antimalarial drugs, as well as other tools, have been helping to offset the malaria burden for years, so Covid-19 wasn’t considered a priority.
Experts agree that the disparity is due to long-standing patterns of which deadly diseases get attention and which don’t. Ballou stated, “Primarily this is the problem you face when trying to develop vaccines that nobody wants to buy for.”
Birkett stated that funding problems plagued every stage of development. Birkett stated that each step of development had to be taken sequentially. “We had the task of generating the data, raising the money and designing the protocol.” Experts worry that funding shortages could also hinder the rollout RTS,S. Ballou said that this is the greatest risk facing the vaccine program right now. According to Policy Cures Research (a global health think tank), funds for malaria vaccine R&D, especially clinical development, have been in decline since 2017. In 2020, they dropped by $21million, which is a 15% drop from the previous year.
However, RTS,S has opened the door to next-generation malaria vaccines. R21, the University of Oxford’s vaccine that showed promising results in Phase II trials (77 percent efficacy), is likely to be next. Greenwood stated that they will be greatly benefited by the delivery system and regulators because everyone is familiar with it. R21 may not be a game-changer, however, because it uses the same underlying formula that RTS,S. Birkett said, “All the data suggests, so far,” that it will be very similar.
BioNTech, a German biotech firm that co-created the Covid-19 first mRNA vaccine, announced in July 2021 plans to use the same technology for a malaria vaccine. Clinical trials are planned for 2022.
If they are safe and effective, the next round of vaccines should be available in far less than 35 years. Birkett stated, “I am very confident” that we will be able to move faster the next time.
This article was originally published by Undark. You can read the original article.
