We finally have malaria vaccines. The next hurdle: Distributing them.

Malaria kills half a million people a year in Africa. We can prevent that — if we act fast enough.

In 2000, nearly 900,000 people died of malaria, the vast majority of whom lived in poorer regions of the world, such as sub-Saharan Africa. It’s one of the biggest public health problems in the world, threatening nearly half the world’s population.

Over the last 20 years, insecticide-treated bed nets, antimalarial medications, and the spraying of homes with insecticides significantly reduced global malaria cases and deaths. And for a time, these interventions helped lower the transmission of the disease in Africa, preventing an estimated 663 million malaria cases in the region between 2000 and 2015.

Still today, half a million people die in Africa from malaria every year, and since the Covid-19 pandemic began, that number has been on the rise.

“Over the past two decades, the collective efforts of the global malaria community have dramatically reduced the global burden of malaria, but progress has stalled in recent years,” wrote Philip Welkhoff, the director for malaria at the Bill & Melinda Gates Foundation, in an email. The foundation invested hundreds of millions of dollars in fighting the disease over the last 20 years. “Challenges like drug and insecticide resistance, stagnant funding, and extreme weather events threaten to set progress back even further.”

But new hope in the fight against malaria arrived two years ago via the world’s first-ever malaria vaccine. In October 2021, the World Health Organization (WHO) recommended the RTS,S vaccine (developed by the pharmaceutical company GSK) for use in Africa. And this April, following preliminary trial results, two African countries approved a second, more effective malaria vaccine: the University of Oxford’s R21 vaccine.

These immunizations round out the world’s malaria-fighting arsenal, but new obstacles arise. Africa’s lack of health care facilities and workers; the multimillion-dollar price tag for distribution; and the expanding scope of malaria-carrying mosquitos all pose a threat to eradication efforts. Now, vaccine manufacturers, charitable organizations, government agencies, and local public health officials have to concentrate on getting shots in arms as equitably and quickly as possible, without forgoing other older methods of malaria prevention.

“Unfortunately, we don’t have anything which has 100 or 90 percent efficacy,” said Thomas Breuer, the chief global health officer of the pharmaceutical company GSK, which created the RTS,S vaccine. “So WHO is saying in the absence of a tool which is highly efficacious, we are working with a toolbox.”

Decades of progress are now at a standstill

Because malaria comes from a parasite, not a virus, creating a highly efficacious vaccine against the infection is extremely difficult. “Malaria is actually a very complex disease,” said William Moss, a professor of epidemiology, international health, and molecular microbiology and immunology at the Johns Hopkins Bloomberg School of Public Health.

There’s a handful of parasites that lead to malaria infections, and they vary in their characteristics. The severity and symptoms of malaria can differ based on the exact species of parasite the individual was infected with. Multiple different mosquito species can transmit these parasites. “That kind of combination makes the epidemiology of malaria very focal,” Moss said. “It can be very different just from one village to another village a kilometer or two away.”

Mosquitoes spread this parasite from one person to another via their bite. The mosquito becomes infected by feeding on someone with a malaria-causing parasite, and then subsequently bites other people, infecting them. Once a malaria-causing parasite enters the body, it travels to the liver, where it can stay dormant for up to a year. The parasite develops in the liver before entering the bloodstream and infecting red blood cells, causing symptoms. If left untreated, an individual could die of the infection.

Despite the challenges malaria’s “complex” nature creates for developing a vaccine, scientists have been trying to develop one since the 1960s. In 2013, the World Health Organization set the ambitious goal of developing a malaria immunization with an efficacy rate of 75 percent by 2020.

The first malaria vaccine — the GSK-developed RTS,S — completed testing in 2019. The shot got into kids’ arms for the first time outside of safety trials in Malawi as part of a WHO-created malaria vaccine implementation program. This pilot program tested the safety of the vaccine and the feasibility of a multi-dose immunization administered after the normal infant vaccine regime. The immunization proved practical, with parents across Malawi, Ghana, and Kenya vaccinating their children and returning for follow-up doses, despite the several — potentially long — journeys to clinics.

As of December 2022, 180,000 children over 5 months old completed all four doses (with over 450,000 children receiving at least one dose). The WHO recommended the RTS,S vaccine for use in October 2021, and in early 2024, the organization expects countries across Africa to begin immunizing with it.

This plan is possible because of Gavi, a global health organization that invests in increasing access to vaccines for low-income countries. Between 2022 and 2025, Gavi is committing $155.7 million to malaria vaccine introduction, procurement, and delivery in sub-Saharan Africa. Gavi funded Ghana, Kenya, and Malawi’s RTS,S post-pilot program vaccination campaigns, and over a dozen countries have applied for the organization’s funding to roll out their own RTS,S campaigns.

But the RTS,S vaccine’s efficacy does not reach WHO’s desired threshold — preventing only around 40 percent of malaria cases. Nevertheless, estimates by the Imperial College in London predict the RTS,S vaccine could save thousands of lives.

Through its multi-dose implementation program, it confirmed that a vaccine requiring multiple visits with health care personnel is feasible in Africa, possibly putting a different, newly developed vaccine in the fast lane for approval. This year, Ghana and Nigeria — Nigeria is the country with the largest share of malaria cases in the world — provisionally approved the Oxford-developed R21 malaria vaccine.

The R21 vaccine prevented 77 percent of cases in phase 2 trials, meeting and exceeding WHO’s desired threshold. Phase 2 trials test for efficacy and safety, but the findings must be confirmed via a final, larger phase 3 trial that tests many more people and is usually randomized. Oxford has yet to publish the results of its phase 3 trials, which have an estimated completion date of December 2023. As such, R21 has not received WHO approval yet; however, there’s hope the process will be swift.

“Whether it’s R21 or others, GSK has paved the way so you don’t need to run another implementation phase in Africa because we have solved that problem,” said Breuer. “I am looking forward to a second vaccine because WHO, Gavi, and UNICEF always want to have more than one vaccine. In case there are shortages with one you can compensate with the other.”

The logistical challenges of delivering malaria vaccines

In 2015, GSK began producing its vaccine but stopped due to WHO wanting to run an additional implementation test. The RTS,S vaccine has a shelf life of about three years and as such could not be stored indefinitely as WHO operated the pilot program. But now that the vaccine is cleared for use, GSK will forge ahead on its commitment to donate as many as 10 million doses of the vaccine.

And ideally, if approved in 2024, the R21 vaccine will add to the supply. The University of Oxford partnered with the largest vaccine manufacturer in the world, the Serum Institute of India, for the production of the vaccine.

Over 400 million children live in Africa, and this number is expected to grow. The RTS,S vaccine is a four-dose regime, and the R21 vaccine is a three-dose regime. Assuming at least half of these children are eligible to receive the vaccine, this means that anywhere between 600 million and 800 million doses of malaria vaccines are needed to fully vaccinate eligible children on the continent.

Overall, UNICEF contracted 18 million doses of the RTS,S vaccine, which is still far fewer than is needed to vaccinate the continent. “That means being very targeted in how we allocate the doses. Our phased approach is designed to target support to areas with greatest need initially, and to expand vaccine use as volumes of available doses increase in the coming years,” said Stephen Sosler, the head of vaccine programs at Gavi, one of the organizations leading malaria vaccine delivery in Africa.

“Many countries have expressed a desire to add the [RTS,S] vaccine to their immunization programs, but supply of the vaccine is currently limited, although it should improve over time,” Welkhoff, the director for malaria at the Bill & Melinda Gates Foundation, told Vox. “Additionally, in part due to supply challenges, the current cost of the vaccine is relatively high.”

A vaccination campaign for all eligible children will cost between $4.8 and $6.4 billion if the vaccine is set at the estimated cost of around $8 a dose. Even the lowest end of this calculation is higher than the GDP of over a dozen African countries.

Malaria has economically devastated Africa, preventing tourism and taking otherwise healthy individuals out of the workforce. Altogether, Africa loses as much as $12 billion in productivity to malaria annually.

If countries can overcome the cost barrier, the logistics of delivery will present another hurdle. “One of the things that WHO required prior to pre-qualification were these demonstration projects in three countries — Ghana, Kenya, and Malawi — to show that they could actually deliver the vaccine to these children. And they have been successful,” said Moss. “But it’s put some strain or additional burden on the immunization system to be able to deliver a malaria vaccine. Those operational challenges will limit the number of children who received a complete schedule.”

Africa already suffers a shortage of health care workers. In Nigeria, where over 31 percent of all malaria deaths occur, there are only 38.9 physicians per 100,000 people. The lack of professionals to administer vaccines, even once they become available, is an additional hurdle that has no quick solution.

“It’s a new vaccine, with a multi-dose regimen that includes different touch points in child immunization schedules,” said Sosler. “ That means working with countries to ensure you’re targeting the right populations, you’re rigorous in follow-up to avoid drop-outs, and you’re training health care workers to transport, store, and administer the vaccine safely and effectively. All of that requires financial and technical assistance.”

It’s important to remember these vaccines cannot stand alone. Immunizations, bed nets, insecticides, antimalarial drugs, and new innovations — possibly a transmission-blocking vaccine — are needed to truly eliminate endemic malaria. “These are additional tools,” Moss said of the vaccines, “not to replace other tools.”

Mosquitoes everywhere

Both the RTS,S and R21 vaccines protect against the parasite, Plasmodium falciparum, the most common cause of malaria in Africa and the one most likely to result in fatal malaria. In Africa, the native Anopheles gambiae mosquito transmits this parasite.

Annual malaria cases will continue to increase because climate change increases the scope of this mosquito, which needs certain temperatures and levels of rainfall to thrive. Due to rising temperatures, places that previously only suffered from seasonal outbreaks are now facing year-long endemics. Additionally, this native mosquito species is developing a resistance to the most widely used and inexpensive insecticide against it.

African countries are also facing the threat of the invasive Anopheles stephensi mosquito. Indigenous to Asia, this mosquito first appeared in Djibouti in 2012. In that same year, the East African country reported only 27 suspected malaria cases. By 2020, Djibouti experienced over 73,000 cases. Today, Ethiopia, Sudan, Somalia, and Nigeria report findings of this invasive mosquito.

This invasive mosquito transmits the malaria-causing parasite across a greater number of climates. It can pass Plasmodium falciparum to humans in climates between about 60 and 99 degrees Fahrenheit. The native African mosquito can only transmit the parasite between about 66 and 86 degrees Fahrenheit.

“The current presence and the possible presence of the Anopheles stephensi [the invasive mosquito] in African countries poses potential health risks since it’s a malaria vector well adapted to urban centers that could cause malaria outbreaks of unprecedented sizes,” said Oswaldo Villena, a research fellow with the Earth Commons at Georgetown University. In rural areas, the native African mosquito dominates. The combination of these species leaves no African region safe from malaria.

The primary concern, said Villena, is that the supply of malaria vaccines will not be produced fast enough to keep up with, let alone counteract, the increasing spread of the disease.

“I don’t know how much time we have with this new invasive mosquito in Africa, and with a temperature increase every year,” Villena said. “It’s a race. There’s a lot of need for funding and research in vaccination and in building new infrastructure to make vaccines.”