The world has been striving to develop a malaria vaccine. The first vaccine to be used has a 56% efficacy or in other words only half of those vaccinated were able to prevent severe infections. Now there seems to be promise of a better vaccine at 77% efficacy developed by Oxford researchers. We look at the numbers behind malaria, the disease itself, and the work that's been done to prevent this deadly infection where more than half of deaths are of children under the age of 5 years old.

Shocking Stats: Malaria is a devastating disease. Spread by mosquitoes (known as malaria vectors), it affects more than 230 million people each year. In 2019, death from malaria totaled 409,000. What is a little sad is that almost 67% (274,000) of those deaths are children under the age of 5 years old. Another glaring statistic is that 94% of all cases are in Africa. These two are interesting stats because since the there is higher exposure in Africa, surviving adults develop partial immunity over time which would limit the severity of symptoms. However, that leaves children under the age of 5 years old in Africa highly at risk of severe symptoms and even death.

Half of all malaria deaths occur in Nigeria (23%), the Democratic Republic of the Congo (11%), United Republic of Tanzania (5%), Burkina Faso (4%), Mozambique (4%), and Niger (4%).

The Agent of Damage: The malaria parasite otherwise known as Plasmodium has 5 different species that cause malaria in humans. Two of them cause the most harm. P.falciparum which accounts for majority of infections and P.vivax which accounts for 75% of infections in the Americas. The vector of choice is the female anopheles mosquito. Bites typically occur between dusk and dawn when the temperature cools.

Friendly reminder not to keep still water outside your house as that is a perfect spot for the mosquitoes to drop their eggs. However, the malaria carrying species are not endemic in the US. Once bitten, it takes about 2 weeks to get the first symptoms of fever, headaches, and chills. Within 24 hours after the first set of symptoms, disease progression picks up quickly to cause severe anemia, respiratory distress due to metabolic acidosis, seizures, and eventually multi-organ failure as your body goes into shock trying to keep up.

Prevention: The two main methods of vector control or managing the mosquito population is through an insecticide-treated mosquito net (ITN) or indoor residual (insecticide) spraying (IRS) done once or twice a year. Next up are anti-malarial drugs such as chloroquine for P.vivax and sulfadoxine-pyrimethamine for P.falciparum, both used to prevent & treat an infection. Travelers, children, immunocompromised individuals such as those with HIV, and pregnant women at high risk are recommended to take multiple doses.

Resistance to anti-malarial drugs has been increasing, leading to the use of other drugs such as mefloquine, doxycycline or Malarone (combination atovaquone/proguanil). Most of these drugs need to be taken 2 weeks prior to travel except for malarone which can be taken 2 days prior. Today, the best anti-malarial drugs are artemisinin-based combination therapies (ACTs) which are sourced from a plant called Artemisia annua or sweet wormwood.

ACT resistance has begun to show up, most severe in the Greater Mekong area which follows the Mekong river and has a population of about 326 million. This prompted the WHO and partner countries to accelerate progress in the last two remaining options to solve this problem.

1. Eliminate all malaria parasites once and for all! The WHO launched a 2030 strategy to eliminate all species of human malaria. Specifically targeted at first, the campaign focused on the Greater Mekong area and was named the Mekong Malaria Elimination (MME) programme. Cambodia, one of the participating countries, essentially launched a very manual effort to distribute mosquito nets, check for fevers every week at each house in high risk areas, and drug administration for those most at risk. Between 2017 and 2020 Cambodia saw the number of P.falciparum infections drop from 3528 down to 72!

Today many countries are malaria free. The process is called Certification of Malaria Elimination and requires three years of no infections.

The list of malaria free countries can be found here. Note that the US was malaria free in 1970 while the UK never had malaria to begin with. We still see about 2000 malaria cases in the US mainly from travelers coming back from sub-saharan Africa. Newer countries to be certified malaria free include the United Arab Emirates (2007), Morocco (2010), Turkmenistan (2010), Armenia (2011), Sri Lanka (2016), Kyrgyzstan (2016), Paraguay (2018), Uzbekistan (2018), Algeria (2019), Argentina (2019) and El Salvador (2021).

2. If you can't eliminate them, then at least build immunity against them! The first and only vaccine to reduce P.falciparum malaria in 4 out of 10 cases over 4 months was the RTS,S/AS01 vaccine. It was tested on 15,000 children in a large scale phase 3 clinical trial with a dosage requirement of 4 separate doses. 12 month follow up demonstrated a 55.8% efficacy. In 2019, the vaccine was introduced into Ghana, Kenya, and Malawi. This vaccine does not work against P.vivax which is seen predominantly outside of Africa.

Since the RTS,S/AS01 vaccine, many others continued to progress in clinical trials. Just recently, a clinical trial conducted by researchers from Oxford for the latest malaria vaccine called R21/MM demonstrated a 77% efficacy over 12 months in 450 children in Nanoro, Burkina Faso. The efficacy will now have to be proven in a larger phase 3 trial which will include 4,800 children.

The naming structure is based on the target protein on the parasite followed by the adjuvant used. The adjuvant is an unrelated protein meant to jump start the general immune response to build a strong immune response specific to the vaccine target. In this case, the adjuvant is called Matrix-M. This is the same adjuvant used in Novavax's Covid 19 vaccine candidate.

Both RTS and R21 (the newer one) are protein based vaccines that target the parasite during the early stages of its life cycle. Unlike a virus that can produce adult clones that burst out of infected cells, the parasite has to go through a full cycle of growth starting as sporozoites which is what these vaccines target. Similar to the RTS vaccine, the R21 vaccine also requires 4 doses which is a challenge when you have people living in remote areas.

The challenge is getting patients to the clinic, or making multiple trips to their homes as part of a humanitarian effort. As we saw with Cambodia's significant drop in malaria infections, prevention is a very hands-on process requiring a lot of human labor that just needs to be done in every house in every high risk region which becomes a multi-year effort once the new vaccine is rolled out.