BEATING MALARIA: WHAT HAVE BEEN THE CHALLENGES AND WHAT ARE THE OPPORTUNITIES

Updated 5 February 2024

What Is Malaria - How, When And Why?

Malaria is a life-threatening disease originating from parasites transmitted to people through infected female Anopheles mosquito bites. According to the World Health Organization (WHO), there were around 228 million cases of malaria and 405,000 deaths in 2018.^[1] Up to 65% of these deaths occur among children under the age of five in sub-Saharan Africa due to increasing resistance of malaria against conventional antimalarial drugs.

Insufficient global health services and international patient care are largely to blame for the problem. This disease is largely a consequence of poverty, where malaria control methods are lacking for high-risk communities.

Over the past decade, there has been good news to be found related to progress made in the fight against malaria. When the strategy shifted from controlling the disease to eradicating it, scientists collaborated with public health players to move forward in a coordinated and focused way, cutting malaria infections by 50 percent.^[2]

Countries Worst Affected By Malaria - What Have Been Their Challenges?

The majority of the countries most affected are in Africa.^[3] Due to a lack of global health services and international patient care, malaria cases worldwide are heavily concentrated in 29 countries, which make up 96% of all instances. Within this group, four nations stand out: Nigeria (27%), the Democratic Republic of the Congo (12%), Uganda (5%), and Mozambique (4%) collectively represent nearly 50% of global cases.^[4] Comparatively, African countries suffered 234 million cases of malaria versus America's 0.6 million reported infections in 2021. Southeast Asia reported 5 million cases, with Eastern Mediterranean infections totaling 6.2 million. The Western Pacific region came in behind Eastern Mediterranean locales, reporting significantly lower numbers, at 1.4 million cases. The root of the problem is money. Insufficient funding has contributed to the dismal infection rate, particularly as it relates to high-risk groups such as mobile community segments or those residing in remote locales.

Mapping The Near End - How It Was Made Possible

When the collective powers of scientists and global health organizations come together at the World Health Organization (WHO) to support eradication planning, initiatives are set into motion to make it happen. There are three major steps that have been taken to map the end of malaria. First and foremost, elimination and management programs have been created and implemented for success in specific settings. Next, ongoing R&D efforts have been funded to create the new tools necessary to fuel successful eradication and control efforts.

How Close We Are To Eradicating It

Unfortunately, progress has been slow as it relates to meeting the optimistic goals established by the World Health Organization after 70 years of waging war against malaria. Additional funding for the purchase of more tools to fight this health problem is mandatory to get back on track to eliminate the malaria threat in the near future. A heavy focus on Africa must be renewed since this area suffers from 96 percent of malaria deaths worldwide. To achieve progress in this area, more funding is needed to purchase medicine, insecticide nets, and other life-saving supplies.

While there is still much to do, there are some successes to celebrate. Twelve countries are now free of malaria. United Arab Emirates, Argentina, Algeria, China, El Salvador, Uzbekistan, Paraguay, Morocco, Sri Lanka, Kyrgyzstan, Armenia, and Turkmenistan are malaria-free. In June 2022, the World Health Organization (WHO) released updated guidelines for the final elimination phase. These guidelines classify interventions into three main categories:

"Mass" strategies, which encompass entire populations within specific geographic regions.

"Targeted" strategies, tailored to people at higher risk of infection.

"Reactive" strategies, implemented as responses to individual cases.

Maintaining the momentum necessary to achieve this goal will save millions of lives and trillions of dollars.

On January 22nd, 2024, Cameroon initiated the world's first routine vaccination program against malaria^[5]. This move marked a significant advancement in the fight against malaria worldwide.

According to the international vaccine alliance Gavi, Cameroon is the first nation to provide doses through a regular program that 19 other nations hope to implement this year, following successful trials conducted in Ghana and Kenya, among other countries. Through 2024–2025, 6.6 million children in these nations are expected to receive malaria vaccinations. According to Gavi, the RTS,S vaccine rollout is expected in May or June 2024.

The Latest on the New Malaria Vaccine

Second to avoiding mosquito bites via repellent, long clothing and bed nets, antimalarial drugs are the mainstay for treatment and prevention. Antimalarial drugs work by killing or inhibiting the growth of the parasites in the blood or liver. Examples of antimalarial drugs include Chloroquine, Mefloquine, Doxycycline, and Artemisinin-based combination therapies. While effective in treating 70-90% of cases, P. Falciparum, the most deadly type of malaria globally, has recently been shown to develop resistance towards antimalarial treatments.

Due to the high mortality rates Malaria leaves in its wake, there has been an urgent need for better preventive measures and more widely accessible treatment options. In recent decades, the WHO has pushed for the development of a safe and effective vaccine that can prevent malaria infection and reduce its transmission. The ideal vaccine candidate would prevent the parasites from entering or developing in the liver or blood or prevent them from infecting other mosquitoes. In theory, this has the potential to rid the planet of malaria once and for all.

Finally, after more than 50 years, effective malaria vaccines have finally been developed and approved for use in all affected areas, with several others waiting to follow.

R21/Matrix-M: The Newly Approved Malaria Vaccine

On October 2^nd, 2023, a new malaria vaccine was approved for use that displays a much higher efficacy than the first approved malaria vaccine, RTS,S/AS01, as well as being cheaper and quicker to produce.

The R21/Matrix-M (R21/MM) vaccine was developed by teams at Oxford University and is being manufactured by the Serum Institute of India. It is essentially a modified version of the RTS,S that targets the liver stage of the parasite, inhibiting it early on during its life cycle and preventing serious malaria symptoms.

Pilot Program and Phase III Trial Results

The vaccine has shown 72-85% efficacy in a phase IIb trial involving 450 children in Burkina Faso^[6], with protection lasting for more than 2 years (up to 80% effective at 1 year).

Following these promising results, a phase III trial was initiated in four African countries: Burkina Faso, Kenya, Mali, and Tanzania, involving 4,800 children.

The results from this trial on the efficacy of the R21/ Matrix-M vaccine have shown approximately 75% of symptomatic malaria cases in young children being prevented in the first year following vaccination.^[7] The vaccine prevented symptomatic malaria cases in children between 5 and 36 months of age when administered before the peak malaria season. In places where transmission occurs year-round, it averted 68% of malaria cases.

R21 Vaccine Approval, Supply Demand and 2024 Rollout

The R21/ Matrix-M vaccine is the second to be made available this year. It has already been approved by regulatory bodies in three West African nations as well as the World Health Organization. Ghana was the first country to approve the R21 vaccine in early 2023, followed by Burkina Faso and Nigeria after the success of the phase III trial. The WHO has recently recommended the vaccine to all at-risk countries and is working with UNICEF and Gavi (the vaccine alliance, a public–private global health partnership) to secure a widespread rollout. UNICEF has agreed to help procure and dispense the R21/MM in an agreement spanning 2024-2028.^[8] The Serum Institute anticipates producing between 180-200M doses per year and has been setting up a facility in Ghana with DEK Vaccines Ltd to speed up production.^[9]

Mechanism of Action

Like the RTS,S, this vaccine also targets CSP, the protein found on the malaria parasite’s surface during the first phase of infection. Unlike the RTS,S, it contains and targets a much larger amount of CSP. There is also less hepatitis B surface antigen present relative to CSP, meaning that the immune system can divert more attention to mounting a defense against malaria sporozoites (stage 1 malaria parasites). These changes are reflected by the improved efficacy of the vaccine.^[10]

The R21 vaccine also makes use of a different adjuvant called Matrix-M, which was shown to elicit twice the immune response to that of AS01. This involves inducing a higher number of antigen-presenting cells at the site of injection, stimulating a much swifter immune response.

Side Effects

As seen with the RTS,S, the R21 elicited similar short-term side effects that are commonly experienced in response to any vaccine and often pass within a few days. Fever, drowsiness, irritability, and loss of appetite were the systemic side effects observed. There are currently few known reports of significant adverse events in those who received the R21/MM vaccines across studies.

RTS,S/AS01: The World’s First Approved Vaccine for Malaria

The first vaccine for malaria was finally approved for use by the WHO in October 2021 after undergoing more than a decade of clinical testing.

Known as the RTS,S/AS01 (or Mosquirix), the first vaccine was developed by GlaxoSmithKline (GSK) in partnership with the PATH Malaria Vaccine Initiative and other collaborators. This vaccine targets the first stage of the parasite’s life cycle in the liver and aims to prevent clinical malaria and severe malaria.^[11]

Results from Phase III trials

RTS,S/AS01 has been evaluated in a large phase III clinical trial involving more than 15,000 children in seven African countries. The results showed that the vaccine reduced the risk of clinical malaria by 39% and severe malaria by 29% in children aged 5-17 months who received four doses over 18 months. The vaccine also reduced the risk of clinical malaria by 27% and severe malaria by 15% in infants aged 6-12 weeks who received three doses along with routine childhood vaccines.^[12]

The RTS,S/AS01 Pilot Program

Based on these findings, WHO recommended in 2015 that RTS,S/AS01 be piloted in three African countries: Ghana, Kenya, and Malawi. The pilot program started in 2019 with the aim of assessing the vaccine’s feasibility, impact on child health and mortality, as well as the effectiveness of current administration systems. Since this time, it has effectively reached more than 1.7 million children,

been well-tolerated, and reduced malaria-related hospitalizations and deaths.

Based on these results and the vaccine’s subsequent approval in 2021, the pilot program is currently being extended to 18 million doses to be administered in 9 other African countries: Benin, Burkina Faso, Burundi, Cameroon, the Democratic Republic of the Congo, Liberia, Niger, Sierra Leone and Uganda. The vaccines are expected to arrive in these countries by the end of 2023, with administration planned by the beginning of 2024.^[13]

How Does the RTS,S Vaccine for Malaria Work?

The mechanism of RTS,S vaccine for malaria is based on targeting the circumsporozoite protein (CSP). This is a major surface protein of the malaria parasite that allows it to invade liver cells during the first stage of infection.^[14]

The vaccine was modeled off of a vaccine against Hepatitis B. Using the hepatitis B surface antigen as a carrier, researchers inserted it with CSP antigens and added it to the adjuvant AS01 (a substance that enhances the immune response). The vaccine stimulates the production of antibodies and T lymphocytes (white blood cells) that can recognize and attack the CSP antigen on the parasite.^[15] 

This can prevent or reduce the infection of the liver cells before the parasites are released into the blood, which is the cause of clinical malaria with all its devasting symptoms. 

The vaccine also induces memory immune cells, which are primed for a long time against one single threat and that can provide long-term protection against malaria. However, the vaccine does not provide complete or lifelong immunity and does not prevent infection or transmission of the parasite. 

RTS,S Side Effects

The most common side effects of RTS,S/AS01 are:

• Injection site reactions, such as pain, swelling, and redness
• Systemic reactions, such as fever, headache, fatigue, and malaise

These side effects are documented to occur within a fraction of individuals who receive any vaccine. They are usually mild or moderate and tend to resolve within a few days.

Complications: Across the clinical trials, an average of 1 in 5000 children who received the vaccine developed meningitis^[16], a rare but potentially fatal inflammation of the membranes that cover the brain and spinal cord. Less frequently observed complications include anaphylactic reactions (severe allergy) and convulsions.

R21/Matrix-M Vaccine Vs RTS,S/AS01 and Antimalarial Drugs

When phase III trial results are compared, the R21/Matrix-M vaccine is known to possess almost double the efficacy than RTS,S/AS01, and a similar efficacy to the best available antimalarial medications, such as artemisinin-based combination therapies. Future results that directly compare the efficacy of each vaccine in the same populations will be required to confirm their differences and whether the R21/MM is truly superior.

Other advantages of the vaccines over conventional antimalarials include:

• Cost-Effectivity. Each dose of the R21 costs between $2 and $4; four doses are needed per person. That is about half the price of the most effective antimalarial medications and each RTS,S dose, which averages less than $9.30.
• Longer Protection. The RTS,S vaccine provides a longer duration of protection than antimalarial drugs, showing sustained efficacy for up to four years after the last dose. Antimalarial drugs only provide protection for a few weeks or months after the last dose. The R21 vaccine is expected to outperform the RTS,S due to the stronger immune effects of the MM adjuvant, although this remains to be tested.
• Lower Transmission Risk. Both vaccines can prevent infection or reduce parasite density in vaccinated individuals, reducing their infectiousness to mosquitoes and lowering the risk of spreading malaria to others. Antimalarial drugs can only treat existing infections and do not prevent new ones.

Each malaria vaccine is expected to become more widely available through the course of 2024, with the aim of combating malaria fully throughout Africa in the years to come.

The Future of Malaria Vaccine Development and Deployment

While the R21/MM vaccine displays a very high efficacy, there isn’t yet a vaccine or medication that can entirely eliminate malaria, provide complete protection or prevent transmission 100%. Both vaccines are currently intended to complement existing malaria prevention and control measures, such as insecticide-treated nets, indoor residual spraying, timely diagnosis and treatment, and periodic preventive treatment for pregnant women and infants.

Research and development of new and improved malaria vaccines is still ongoing for improved protection, longer duration and broader coverage against different strains and stages of the parasite.

There are several other malaria vaccine candidates that are in different stages of development and testing, including:

• PfSPZ Vaccine: This vaccine uses whole sporozoites, the form of the parasite that infects the liver, that have been weakened by radiation. The vaccine is administered by injection and aims to induce immunity against the liver stage of the parasite. The vaccine has shown between 54-100% protection across participants in a small clinical trial^[17] and is currently being tested in larger trials in Africa and Asia.
• mRNA Vaccines: Other vaccines in development use messenger RNA (mRNA) molecules that encode proteins from the parasite. The mRNA is delivered by lipid nanoparticles and instructs the cells to produce the proteins, which then trigger an immune response. The mRNA vaccines can target different stages and strains of the parasite and can be rapidly designed and manufactured. Several mRNA vaccines for malaria are being developed by different groups, such as BioNTech, Moderna, and CureVac.^[18]

Conclusion

Malaria is a deadly disease that affects millions of people worldwide every year. Prevention and control are essential to reduce the burden of disease and save lives. With the ultimate goal of eradicating malaria from the world, the WHO has been collaborating with global stakeholders and institutions to devise an ultimate solution.

In recent years, the first vaccine for malaria, RTS,S/AS01, was approved for use and has recently been followed by a second, the R21/Matrix-M vaccine. The R21/MM has been shown to be up to twice as effective as the RTS,S, with an improved mechanism of action that disables the malaria parasite early on during infection. The results bode well for preventing millions of malaria-related deaths annually and eventually for devising a cure.

The development of a malaria vaccine has been a long and challenging journey, yet also a remarkable achievement of science and collaboration. Other malaria vaccines are currently under development that are sure to follow.

If you are traveling to an area that is prone to malaria, here are some tips to stay safe

• There are several effective preventive drugs. Consult your doctor or travel clinic for the best one for you
• Wear protective clothing such as long trousers and long-sleeved shirts
• Use mosquito repellents directly on the skin
• Use long-lasting insecticide sprays
• Place wire or gauze screens on all doors and windows.
• Use mosquito netting over the beds

Consult your doctor and request a malaria test if you develop any flu-like symptoms during or after visiting a malaria-prone area. Remember, malaria is treatable, so talk to your doctor if you have any concerns.

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