Results from a phase 1 clinical trial looking at the use of low-dose subcutaneous or intravenous monoclonal antibody to prevent malaria have been published in the New England Journal of Medicine (NEJM).
Prof Eleanor Riley, Professor Emerita, Immunology and Infectious Disease, Institute of Immunology and Infection Research, University of Edinburgh, said:
“The relative ease with which vaccines were developed against COVID-19 sits in stark contrast with the situation for diseases such as HIV, tuberculosis and malaria. Despite decades of research, and many billions of dollars and pounds spent, we still lack highly effective vaccines for these and many other diseases that are highly prevalent, especially in Africa, Asia and South America.
“In the case of malaria, the only vaccine to be approved for routine use offers, at best, 35% protection against symptomatic disease (but not against infection per se) for 12 -18 months. Whilst useful, this vaccine will not reduce the reliance of malaria control programmes on antimalarial drugs and mosquito control.
“Against this background, the results of this small scale clinical trial showing that a single dose of monoclonal antibody, administered by either subcutaneous or intravenous injection, can be highly protective against infection (and thus disease) is important. The antibodies target an Achilles’ heel of the malaria parasite, blocking the interaction between the sporozoite stage of the parasite injected by the mosquito and the liver cell that it needs to invade in order to establish infection.
“In addition to identifying a suitable antibody, the researchers also modified the antibody, via genetic engineering, to make it more resistant to clearance by our body’s waste disposal systems and thereby extending its useful life. The researchers predict that sufficiently high titres of antibodies could be maintained for 6-12 months after a single injection.
“In theory, a single antibody injection given annually just before the onset of the peak malaria season could completely protect an individual from infection and substantially reduce the burden of disease and death from malaria. Similarly, a single shot of antibody may protect travellers for up to 6 months, removing the need to take preventive medications.
“Despite its promise, this research is still at an early stage. The trial was conducted in healthy volunteers in the USA who were deliberately infected with sporozoites 4-6 weeks after receiving the antibody treatment. Trials in malaria endemic communities are now needed to determine how well the antibodies work in a more varied population with repeated exposure to infection over many months. If the results of these trials are encouraging, challenges such as manufacturing, cost, cold chain distribution and safe administration in resource constrained settings will need to be overcome. Safety data from the trial were in line with expectations from similar studies and as monoclonal antibodies are part of mainstream care for several chronic conditions, gaining regulatory approval is unlikely to be problematic.”
Prof Sir Brian Greenwood, Professor of Tropical Medicine, London School of Hygiene & Tropical Medicine, said:
“Progress in control of malaria has stalled during the past few years, especially in several countries in sub-Saharan Africa which have the highest burden of the infection, despite widespread deployment of effective diagnosis and treatment, chemopreventive and vector control strategies. Therefore, additional tools are needed to reinstate the progress in malaria control that had, until recently, been achieved during the past two decades. WHO has recently approved the deployment of the RTS,S/AS01 vaccine but this vaccine provides only partial protection, as do the other two most developed malaria candidate vaccines, R21 and PfSPZ. Thus, the report by Wu et al. in a recent issue of the New England Journal of Medicine that a high level of protection can be achieved following a single injection of a monoclonal antibody is an important development with great promise for malaria control.
“In the proof of principle study conducted by Wu et al., 18 volunteers received the monoclonal antibody L9LS, which targets a conserved region of the circumsporozoite protein on the surface of the malaria sporozoite, the same protein targeted by the RTS,S/AS01 and R21 vaccines. Three groups of five healthy volunteers received different doses of the monoclonal antibody by intravenous infusion and one group by sub-cutaneous injection. Serum antibody concentrations were measured over the next 56 days and modelling indicated that the antibody had a half-life of around two months. Six weeks after administration of the monoclonal antibody, 17 of the volunteers and six controls were exposed to bites by Anopheles stephensi mosquitoes infected with Plasmodium falciparum. All the controls developed malaria but only two of the volunteers who received the monoclonal antibody developed malaria, one in the lowest dose intravenous group and one in the group who received the antibody subcutaneously. The injections were well tolerated and no significant safety signals were observed. Encouraged by these promising results, trials of the L9LS are now underway at two sites in sub-Saharan Africa.
“Provided that comparable results can be obtained in populations naturally exposed to malaria to those found in experimentally infected volunteers when given by sub-cutaneous injection, monoclonal antibodies could have a major role to play malaria control. The kinetic studies undertaken during the trial suggest that a single injection will give a high level of protection for three to six months and so monoclonal antibodies are likely to be of greatest use in populations where a high level of protection can be achieved for a relatively short period of time. The WHO has recently outlined the situations in which anti-malaria drugs given prophylactically for a relative short period can be of most benefit in populations of malaria endemic countries. These include pregnancy, the first two years of life, areas where malaria is transmitted for just a few months each year, and children discharged from hospital after treatment for anaemia, a group whom mortality during the following few months is very high. These are some of the situations in which a monoclonal antibody giving several months of high level protection could be especially useful as well as in travelers to an endemic area and as a component of a malaria elimination campaign.
“A concern over the potential value of monoclonal antibodies for malaria control in endemic countries is their cost. However, further malaria monoclonals under development may be more potent than L9LS and progress is being made on more economic ways of manufacturing monoclonal antibodies at scale. In an accompanying editorial, Wells and Donini suggest that with these advances it should be possible to produce a malaria monoclonal at a cost comparable to that of a malaria vaccine.
“The long term goal for the immunological approach to the control and final elimination of malaria must be the development of a malaria vaccine that provides a long-term high level of protection against malaria but this is a challenging goal and in the meanwhile monoclonals could have a very important role. More clinical trials are now needed to determine the most effective ways that malaria monoclonal antibodies can be used to re-ignite the current stalled progress in malaria control.”
‘Low-Dose Subcutaneous or Intravenous Monoclonal Antibody to Prevent Malaria’ by R.L. Wu et al. was published in the New England Journal of Medicine at 22:00 UK time on Wednesday 3 August 2022.
Prof Eleanor Riley: “EMR is a member of the scientific consultants group of the USAID Malaria Vaccine Development Programme and the external advisory committee of the Malaria Vaccine Immunity and Efficacy programme of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. She had no involvement with the funding, design or execution of this study.”
Prof Sir Brian Greenwood: “I am in regular discussion with Dr Seder about his work and we are planning some potential future studies to take this forward but I had no part in the study published in the NEJM.”