Malaria hits pregnant women and children especially hard.

by Alexa C. Kurzius 

Malaria killed 660,000 people in 2010, and 90% of those who died were children under the age of 5. Yet in spite of these terrible numbers and considerable malaria treatment and prevention efforts, a vaccine against malaria remains elusive.

It’s not for lack of trying. Researchers and large funding organizations have been working for years on vaccines that target the liver, blood, or placenta — all sites in the human body where the malaria parasite invades. Even as researchers keep working and hoping for a successful vaccine to reduce transmission and fatalities, malaria continues its death march through disease-endemic areas of the world, primarily in sub-Saharan Africa, where children and pregnant women are hit the hardest.

Vaccines: successes and setbacks

A new hope

Despite these complexities, new developments keep hope for a vaccine alive. Although it has only been tested in a small number of patients, PfSPZ, the malaria vaccine candidate developed by Maryland-based biotechnology company Sanaria Inc., showed complete disease protection in the six patients who received the highest dose. Using a live form of the parasite weakened by radiation, the vaccine is designed to produce an immune response in the liver. This prevents the parasite from moving into the bloodstream, which is the stage where people experience flu-like symptoms.

Unlike other malaria vaccines in development, PfSPZ is given intravenously rather than under the skin or into the muscle. “It’s not what is usually done for vaccines,” says Stephen Hoffman, lead researcher on the study and founder of Sanaria, “but we don’t see it as an obstacle.” He likens PfSPZ’s intravenous administration to having your blood drawn, but with a smaller needle. Sanaria plans to use PfSPZ in mass vaccination campaigns, he says, training those who would give the vaccine. Hoffman based his vaccine on research from the 1970s, along with his own experiences in the 1990s, when he worked to develop malaria vaccines for the United States Navy.

Calling the work “an exciting step forward,” Andrew Read, a malaria researcher from Penn State University who not associated with Hoffman’s work, says it “really is very good.” But he cautions about the practicalities of administering the vaccine in the developing world, which, he says, is “a bit hard to imagine at the moment.” The vaccine needs to be stored in liquid nitrogen, and the intravenous method would require some training.

Storage and administration logistics aside, before this vaccine can be approved, it needs to be tested in large populations. Trials in Tanzania, Mali, Equatorial Guinea, Germany, and the United States are expected to begin within the next 6 to 8 months, meaning that, according to reporting done by NPR, the earliest the vaccine could become available would be late 2017 or early 2018. Also, the manufacturing of the vaccine needs a boost: Currently, it’s made by manually removing an infected mosquito’s salivary glands. Sanaria has been partnering with the Harvard School of Engineering to help develop methods for automated dissection so that the vaccine can be produced more efficiently.

Mixed signals

Another candidate that’s pretty far along in its development is RTS,S/AS01, a vaccine developed by GlaxoSmithKline (GSK) and the PATH Malaria Vaccine Initiative (MVI). GSK has funded $300 million so far and the MVI has funded $200 million through grants received from the Bill & Melinda Gates Foundation. Its effects in clinical trials thus far have been modest, with discrepancies in results across the two age groups studied that have left some researchers puzzled and others disappointed.

This maddeningly inconsistent vaccine originated from a 1987 discovery at the Walter Reed Army Institute of Research in Silver Spring, Maryland. Because infection first starts in the liver, it is reasonable to design malaria vaccines that target proteins within this organ. As such, the RTS,S/AS01 vaccine, like the Sanaria candidate, is intended to induce an immune response in the liver before the parasite progresses to the blood. “The holy grail of any malaria vaccine is being able to stop the parasite when it initially infects the liver,” says Nathan Schmidt, a malaria researcher from the University of Tennessee.

Conducted in 11 research centers in 7 African countries, the RTS,S/AS01 vaccine trial followed over 15,000 infants and young children. The first study results on young children aged 5 to 17 months were published in 2011. This study showed that the 3-dose vaccine was effective in reducing malaria cases by 56%. At that time, these results showed promise.

The 2012 published results on infants 6 to 12 weeks of age were less favorable, showing only a 31% rate of vaccine effectiveness. This outcome was a disappointment compared to the earlier findings in older children, and researchers at MVI, GSK, and the African centers “are looking for answers as to what happened to this younger group,” says a source at MVI. This organization, along with GSK, is evaluating longer-term safety data, including the effects of a booster shot, and expects to publish results in 2014.

More recently, one center in Kenya published their efficacy results in March 2013 for RTS,S/AS01. Although the vaccine initially reduced malaria infection by 44% within the first year of vaccination, it ended up being ineffective against the disease after four years. A source at MVI points out that the trial took place in just one study center and that researchers are looking across trial sites in their ongoing analyses.

A different tack

Another type of malaria vaccine that has been more challenging to develop is one that targets the blood stage of infection. After the parasite escapes from the liver and enters the blood stream, it infects and multiplies within red blood cells. A blood-stage malaria vaccine would prevent the parasite from getting into red blood cells and ideally be used in combination with vaccines like RTS,S.

Back in 2011, researchers from the Jenner Institute at the University of Oxford identified a molecule called RH5, which allows the parasite to enter red blood cells. Using animals as a model for humans, the scientists showed that their vaccine triggered an immune response and blocked RH5, which locked the parasite out of cells. At that time, researchers were hopeful that they would be able to begin safety tests and human trials within the next few years. Since then, they have published additional research suggesting that a more effective vaccine may come from combining the RH5 target with a second target.

Beyond a vaccine’s reach?

Even for people who’ve had malaria, natural immunity to the disease doesn’t confer an ironclad defense. “You never get complete protection” against malaria, says Read. This is because there is a time-dependent waning of antibody levels that initially develop after a natural infection.

Another critical issue with malaria, like so many other communicable diseases, is its transmission rates. Mosquitos spread the disease in saliva, picking up the parasite from the blood of an infected person. In particular, the Anopheles gambiae species is a power player in Africa’s malaria transmission because of its preference for human blood and its ability to breed in small puddles of water left by a human footprint. “To knock out disease, you need to stop transmission, and that requires an extraordinarily effective public health intervention when transmission rates are high,” says Read.

Vaccines are only one type of intervention in the chain of malaria infection, which also includes distribution of insecticide-treated bed nets and anti-malaria drugs. Bed nets were used about 85% of the time in the RTS,S studies, and the WHO estimates that 150 million bed nets are needed to protect the 780 million people at risk in sub-Saharan Africa alone. Anti-malaria drugs, like artemisinin-based combination therapies, are also popular and have been distributed in endemic countries through public and private sectors, according the WHO. But insecticide-treated bed nets and malaria drugs are becoming less effective, according to Read, as the mosquitos are becoming resistant to the insecticide and the drugs. In addition, evidence from a 2012 study showed that the malaria-transmitting Anopheles funestus mosquito changed its biting habits from the middle of the night to early morning, which suggests a possible evolutionary response to bed nets, or at the very least, a change in behavior.

Read is also wary of the possibility that vaccine development could place evolutionary pressure on the parasite or lead to an increased prevalence of more virulent versions. In a 2012 research article, Read’s lab showed in animal studies that more virulent, infectious strains of the parasite might circulate at higher frequencies if the population is vaccinated.

He considers RTS,S a “leaky” vaccine because even with the shots, the parasite could still possibly escape into the blood. For parasites like malaria, Read says, you “will never expect a vaccine to be very good because the natural immunity is not very good.”

Maternal involvement?

One reason for the mixed and underwhelming results is that researchers aren’t exactly sure which pathways in the body to exploit for a vaccine against malaria. “There is some evidence that malaria immunity is passed on from mother to child,” says Frank Baiden, a physician and malaria researcher based in Ghana, noting that “in endemic areas, malaria is not as common in children less than 3 months of age.” Yet as babies grow, maternally derived antibodies become less potent, which can lead to increased risk of malaria infection, says Ali Salanti, a malaria vaccine researcher at the University of Copenhagen in Denmark.

In spite of this possibility of protection, malaria infection during pregnancy isn’t a desirable scenario. Pregnant women and their unborn children are particularly vulnerable to placental malaria, a distinct form of the infection that has especially harmful outcomes. This illness arises when a pregnant woman has a blood-stage malaria infection and parasite-infected red blood cells hook onto the placenta for the entire duration of the pregnancy. Some vaccine researchers are developing candidates to target placental malaria, as mothers can develop this disease regardless of their past history of malaria disease—see “waning immunity,” above.

Once a mother has the infection, the placenta becomes a “reservoir of malaria parasites,” says Salanti, whose research focus is on placental malaria vaccines. The disease can lead to flu-like symptoms, severe anemia, and an inflammation of the placenta, which reduces the transfer of nutrients from mother to fetus. Low birth weight is common in mothers with placental malaria, as is the incidence of stillbirth. “The earlier the parasite binds the more harm it causes,” says Salanti.

About 10 years ago, researchers including Salanti discovered a protein in the malaria parasite that binds to the placenta, causing the pregnancy-related disease. They’ve since published their findings and have been developing a vaccine to protect both mother and child by interrupting infected red blood cells from binding to the placenta. Initially funded by the Gates Foundation and now funded by the European Union and ExpreS2ion Biotechnologies, a Danish biotech company, the vaccine is being tested for safety in a small group of non-pregnant women in clinical trials in Benin and Germany. If all goes well, larger clinical trials testing for the vaccine’s effectiveness will occur in the next few years.

Developing a successful placental malaria vaccine would have a “double effect,” Salanti says. It would protect “the mother and the unborn child.” The goal of this vaccine is to increase the birth weight of newborns by about one pound. “It’s a very bad start to be born of low birth weight,” he says, because low birth weight can bring on other health problems. Additionally, Salanti and his colleagues are in the early stages of developing a combined placental malaria vaccine and an HPV vaccine, which will help protect women from placental malaria and cervical cancer.

For doctors who, like Baiden, treat so many patients with the disease, a successful vaccine cannot come quickly enough. “It remains a challenge in international health to get all pregnant women and all children under 5 … access to the various malaria prevention interventions,” he says. Despite continuing concerns and some setbacks, many researchers commend the work that has been done so far. “An enormous infrastructure” was created, says Schmidt, “that lays the groundwork for subsequent malaria vaccine clinical trials.” More importantly, these results provide hope for people living in endemic areas. All of the developments are “still good news for anybody” who treats malaria, says Baiden. “We can only make progress.”

Alexa C. Kurzius is a health and science writer living in New York City. She previously wrote at Double X Science about how modern technology affects our communication.