Why Did It Take 35 Years for the World To Get a Malaria Vaccine?
- The WHO approved the first
malaria vaccine in October 2021 and it was hailed as a milestone. Dubbed
RTS,S, it promises a 30% reduction in severe malaria in fully vaccinated
children.
- However, the core ingredient
of the vaccine is almost 35 years old, and researchers have known since
the late 1990s that the formula was somewhat effective at protecting
against malaria.
- When COVID-19 vaccines were
developed and authorised in less than a year, the delay for malaria raises
a question: why did a vaccine for a leading global killer take so long to
arrive?
- The people who are affected by
malaria, “they’re not Europeans, they’re not Australians, they are poor
African children,” said Ashley Birkett, director of the malaria vaccine
initiative at PATH.
- The malaria parasite has a
complex life cycle with at least three stages. A vaccine developed against
one stage would only work then, and not against the one before or next.
When the
WHO approved a malaria vaccine for the first time in October 2021, it was
widely hailed as a milestone. “This is a historic moment,” said WHO
director-general Tedros Adhanom Ghebreyesus in a statement that month.
The
vaccine – dubbed RTS,S – promises a
30% reduction in severe malaria in fully vaccinated children. In 2020, a
research team estimated that
each year, the vaccine could prevent between 3 and 10 million malaria cases,
and save the lives of 14,000 to 51,000 small children, depending on how it’s
implemented.
What those
plaudits often failed to note, though, was that the core ingredient of the
path-breaking vaccine was actually almost 35 years old – and that researchers
have known since the late 1990s that the formula was probably somewhat
effective at protecting against malaria.
At a time
when COVID-19 vaccines were developed and authorised in less than one year, the
delay for malaria raises a question: Why did a vaccine for a leading global
killer take so long to arrive? According to researchers involved in the
development of RTS,S, the answer involves the challenges of developing a
vaccine against a vexing parasite – and the chronic lack of urgency and funding
behind malaria research, which stymied the logistics of research trials at
every step.
The people
who are affected by malaria, “they’re not Europeans, they’re not Australians,
they are poor African children,” said Ashley Birkett, director of the malaria
vaccine initiative at PATH, a non-profit global health organisation.
“Unfortunately, I think we have to accept that that is part of the reason for
the lack of urgency in the community.”
Researchers
had been searching for a malaria vaccine since the late 1960s. In 1980,
they identified a
protein that is abundant on the parasite’s surface, called circumsporozoite
protein, and realised that a vaccine directed against this protein might grant
immunity. After US government researchers sequenced the
gene for the protein in 1984, the military asked them to develop a malaria
vaccine to protect troops overseas. Government officials then enlisted Smith,
Kline & French, a precursor company to the pharmaceutical giant
GlaxoSmithKline, to help.
The work,
experts recalled, was extremely challenging. The malaria parasite has a
notoriously complex life cycle with at least three distinct stages once it’s
inside humans, and it is “actually changing clothes during the evolution,
during the cycle,” said Lode Schuerman, the scientific affairs director for
GSK’s global health vaccines program. Any vaccine developed against a
particular stage would have to stop the infection then, and would not work if
the parasite has advanced to the next stage. Moreover, basic tools that
researchers use today to speed up vaccine development did not yet exist.
More than
a dozen attempted vaccines based on the circumsporozoite protein failed. The
exception was RTS,S. In the late 1980s and early 1990s, the team figured out
various technical details, and a 1998 trial in Gambia, involving 250 men, found that
the vaccine prevented 34% of infections.
“That was
really the start of RTS,S,” said Brian Greenwood, an infectious disease expert
at the London School of Hygiene and Tropical Medicine who was involved in the
Gambia trial.
Still,
attention to the vaccine, Greenwood recalled, was driven more by intellectual
interest than a sense of medical urgency – at least for the broader public,
beyond American troops. “I don’t think there was any sort of push. It was done
by people who were more academics and interested in the immunology,” he said.
“It wasn’t seen as a public health issue.”
And,
people involved in the vaccine’s development told Undark,
the promising shot was about to run into a whole new set of problems: the
myriad tribulations that come with testing a vaccine that doesn’t have a
commercial market.
In 1999,
Ripley Ballou, a vaccinologist who then worked at the Walter Reed Army
Institute of Research, flew to Europe to meet with GSK executives. “I was still
in the Army at the time,” he recalled, “and we were there in our uniforms in
Belgium.” In a conference room with long tables, Ballou and his colleagues from
GSK sat down and presented their findings from the Gambia trial. “We had this
glimmer of hope that came from this study that says, ‘you know, what, something
is happening here, and we think we really need to take it to the next step,’”
he said. And that next step would be to trial the vaccine in the group who
would most benefit: children.
GSK agreed
to go forward – provided Ballou and his colleagues could come up with some
additional funding from a partner organisation. There was a high risk the
project would fail; even if it did succeed, GSK could expect little financial
reward. And the US military was no longer interested in RTS,S, unconvinced the
efficacy would do enough to protect the troops.
Instead,
the partner organisation that funded the work turned out to be the Malaria
Vaccine Initiative at PATH established just a year earlier through a grant from
the Bill and Melinda Gates Foundation.
As the
vaccine makers began launching trials in African countries, they soon realised
that the task of testing the vaccine was going to be far from easy. There were
a lot of logistical issues, said Ballou. “We had to go and there would be a building
with nothing in it, just a concrete shell, and we had to turn it into a
laboratory,” he recalled. “That took time, that took money.”
These
trials were also aimed at young infants and small children, and so the phase I
and II trials, which look at the shot’s safety and efficacy, had to be first
conducted in adults, then in older children, and finally in small children –
optimising the dosage against side effects for each age group before moving on.
“All that process took about 10 years,” said Greenwood.
The
promising results from
phase II trials – in which infants saw a 65.9% reduction in the rate of
infection compared to the control group in the months after the third dose –
led to a large-scale phase III trial, which did not begin until 2009. There was
a steep learning curve for designing the trial, Ballou said, “Nobody had ever
done a malaria vaccine trial at this scale.”
The phase
III trials ran from 2009 to 2014 in seven sub-Saharan African countries. They
enrolled over 15,000 children. And the results were promising – so much so that
GSK began preparing a manufacturing facility for the shot, according to
Schuerman.
But in
October 2015, a WHO review of the phase III trial data found that the rate of
meningitis was higher in the vaccinated group than the control and death was
higher among girls who had received a vaccine, although whether it was linked
to the shot wasn’t clear. To address these issues and to test the vaccine in a
broader real-life setting, the WHO asked for an even bigger trial. This announcement came
out of the blue, said multiple scientists. “We had to close down and put on
hold the whole manufacturing side,” said Schuerman. Instead, he added, once
again, the vaccine team was tasked with the slow work of setting up clinical
trials: seeking funds, selecting countries for the implementation, and hiring
people to conduct the trial.
Today,
most researchers agree that the additional study was warranted. “Given the
attitude towards vaccines globally, it was important to make sure that we ruled
out any potential safety issues,” said Wongani Nyangulu, a physician who leads
a phase IV study site in Southern Malawi.
It took
four years to launch the trial. Eventually, 900,000 children in Ghana, Malawi,
and Kenya received the vaccine. After reviewing the results, the WHO recommended the
vaccine for widespread use in areas of moderate to high malaria transmission in
October 2021. In December, GAVI, the global agency that funds and distributes
vaccines in poor countries, announced it
would invest $155.7 million in an RTS,S rollout.
More than
20 years after the first promising trials, RTS,S was ready for widespread use.
§
By the
time RTS,S was approved, vaccines for another global killer, COVID-19, had
already been developed and authorised around the world – less than two years
after the virus emerged.
The apparent
disparities have frustrated some researchers in sub-Saharan Africa. “If the
same energy and resources were directed towards malaria vaccine development as
has been the case for COVID-19, then malaria could be eradicated,” wrote
Damaris Matoke-Muhia, a scientist at the Kenya Medical Research Institute, in
an essay for
the global development site SciDev.Net last
August. (At the time, she noted, malaria was killing more people on the
continent than COVID-19.)
Other
African researchers have also noted the discrepancy. Deus Ishengoma, a malaria
expert at the National Institute for Medical Research in Tanzania, noted that,
considering COVID, it would be “really bad if the world now closes their eyes
for diseases like malaria.” The speed of development for the COVID-19 vaccine,
he added, meant “we’ll never have a justification or excuse of not making a
vaccine for malaria in the next 10 years.”
Other
experts cautioned that drawing comparisons between the vaccines is not entirely
fair. “COVID is a much easier target for a vaccine,” said Birkett, the PATH
executive. Malaria, he added, “is probably an order of magnitude more
difficult.” The efficacy of RTS,S, several experts said, likely also slowed
down the process. And antimalarial drugs and other tools have long helped
offset the burden of malaria, said Birkett, so the vaccine wasn’t a priority in
the same sense compared to COVID-19.
Still,
experts said, the disparity reflects longstanding patterns in which deadly
diseases receive attention – and which do not. “Primarily, this is the problem
that you face when you’re trying to develop a vaccine that nobody wants to pay
for,” said Ballou.
The
funding woes plagued each and every step of development, said Birkett. “We had
to go very sequentially, step by step by step, generate the data, go and raise
the money, design the protocol.” Several experts worry that funding shortfalls
will also hamper the rollout of RTS,S. This is the biggest risk the vaccine
program faces right now, said Ballou. Funds for malaria vaccine R&D –
especially for clinical development – have been on a downward trend since 2017,
and in 2020 dropped by $21 million, a 15% drop from the earlier year, according to
Policy Cures Research, a global health think tank.
The
development of RTS,S, however, has paved the way for next-generation malaria
vaccines. The University of Oxford’s R21 vaccine, which showed a
promising 77% efficacy in phase II trials, is probably next in line. “They are
going to benefit tremendously from the delivery system and the regulators, as
everybody is used to it,” said Greenwood. Still, R21 might not be a game
changer, as it’s based on the same underlying formula as RTS,S, said Birkett,
and “all the data suggests, so far, it’s going to be very similar.”
In July
2021, BioNTech, a German biotech company which co-created the first mRNA
COVID-19 vaccine, also announced plans to use the same technology to develop a
malaria vaccine, with clinical trials planned for 2022.
The next
round of vaccines, should they prove safe and more efficacious, should take far
fewer than 35 years to come to market. “I’m very confident,” said Birkett,
“that we can go faster next time.”
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