DNA vaccine against malaria: a long way to go

Vaccination is the attempt to mimic certain aspects of an infection for the purpose of causing an immune response that will protect the individual from that infection. Malaria, a disease responsible for immense human suffering, is caused by infection with Plasmodium spp. parasites, which have a very complex life cycle--antigenically unique stages infect different tissues of the body. It is a parasitic disease for which no successful vaccine has been developed so far, despite considerable efforts to develop a subunit vaccine that offers protective immunity. Due to the spread of drug-resistant malaria, efforts to develop an effective vaccine have become increasingly critical. DNA vaccination provides a stable and long-lived source of protein vaccine capable of inducing both antibody- and cell-mediated immune responses to a wide variety of antigens. Injected DNA enters the cells of the host and makes the protein, which triggers the immune response. According to present needs, the flexibility of DNA vaccine technology permits the combination of multiple antigens from both the preerythrocytic and erythrocytic stages of malaria parasite. DNA vaccines with genes coding for different antigenic parts of malaria proteins have been created and presently some of these are undergoing field trials. The results from these trials will help to determine the likelihood of success of this technology in humans. This review presents an update of the studies carried out in malaria using DNA vaccine approach, the challenges, and the future prospects.     

DNA Vaccine Against Malaria: A Long Way To Go

Vaccination is the attempt to mimic certain aspects of an infection for the purpose of causing an immune response that will protect the individual from that infection. Malaria, a disease responsible for immense human suffering, is caused by infection with Plasmodium spp. parasites, which have a very complex life cycle — antigenically unique stages infect different tissues of the body. It is a parasitic disease for which no successful vaccine has been developed so far, despite considerable efforts to develop a subunit vaccine that offers protective immunity. Due to the spread of drug-resistant malaria, efforts to develop an effective vaccine have become increasingly critical. DNA vaccination provides a stable and long-lived source of protein vaccine capable of inducing both antibody- and cell-mediated immune responses to a wide variety of antigens. Injected DNA enters the cells of the host and makes the protein, which triggers the immune response. According to present needs, the flexibility of DNA vaccine technology permits the combination of multiple antigens from both the preerythrocytic and erythrocytic stages of malaria parasite. DNA vaccines with genes coding for different antigenic parts of malaria proteins have been created and presently some of these are undergoing field trials. The results from these trials will help to determine the likelihood of success of this technology in humans. This review presents an update of the studies carried out in malaria using DNA vaccine approach, the challenges, and the future prospects.     

Malaria vaccine development: progress and challenges

A safe and effective malaria vaccine would contribute greatly to the control and prevention of the disease. Although a review of global activity in malaria vaccine development does reflect significant activity, progress has remained slow. This article discusses the current vaccine candidates, with emphasis on those in the clinic, and explains the numerous challenges to making and evaluating malaria vaccines, which have resulted in only a few approaches being adopted and repeatedly evaluated. Against a parasite with more than 5200 genes, the lack of definitive knowledge regarding the nature of protective immunity and absence of reliable surrogates of protection are among the key challenges to a rational evaluation and prioritization of candidate vaccines. Pursuing the current R&D strategies may not result in the availability of a vaccine with characteristics suitable to impact significantly on disease morbidity in developing countries. Therefore, it is critical that the main challenges to malaria vaccine development be unambiguously identified and collectively addressed.     

Pre-erythrocytic malaria vaccines: towards greater efficacy

The complex life cycle of the malaria parasite Plasmodium falciparum provides many options for vaccine design. Several new types of vaccine are now being evaluated in clinical trials. Recently, two vaccine candidates that target the pre-erythrocytic stages of the malaria life cycle - a protein particle vaccine with a powerful adjuvant and a prime-boost viral-vector vaccine - have entered Phase II clinical trials in the field and the first has shown partial efficacy in preventing malarial disease in African children. This Review focuses on the potential immunological basis for the encouraging partial protection induced by these vaccines, and it considers ways for developing more effective malaria vaccines.     

Vaccines against malaria

There is no licenced vaccine against any human parasitic disease and Plasmodium falciparum malaria, a major cause of infectious mortality, presents a great challenge to vaccine developers. This has led to the assessment of a wide variety of approaches to malaria vaccine design and development, assisted by the availability of a safe challenge model for small-scale efficacy testing of vaccine candidates. Malaria vaccine development has been at the forefront of assessing many new vaccine technologies including novel adjuvants, vectored prime-boost regimes and the concept of community vaccination to block malaria transmission. Most current vaccine candidates target a single stage of the parasite's life cycle and vaccines against the early pre-erythrocytic stages have shown most success. A protein in adjuvant vaccine, working through antibodies against sporozoites, and viral vector vaccines targeting the intracellular liver-stage parasite with cellular immunity show partial efficacy in humans, and the anti-sporozoite vaccine is currently in phase III trials. However, a more effective malaria vaccine suitable for widespread cost-effective deployment is likely to require a multi-component vaccine targeting more than one life cycle stage. The most attractive near-term approach to develop such a product is to combine existing partially effective pre-erythrocytic vaccine candidates.     

Towards a blood-stage vaccine for malaria: are we following all the leads?

Although the malaria parasite was discovered more than 120 years ago, it is only during the past 20 years, following the cloning of malaria genes, that we have been able to think rationally about vaccine design and development. Effective vaccines for malaria could interrupt the life cycle of the parasite at different stages in the human host or in the mosquito. The purpose of this review is to outline the challenges we face in developing a vaccine that will limit growth of the parasite during the stage within red blood cells--the stage responsible for all the symptoms and pathology of malaria. More than 15 vaccine trials have either been completed or are in progress, and many more are planned. Success in current trials could lead to a vaccine capable of saving more than 2 million lives per year.     

The Evolutionary Consequences of Blood-Stage Vaccination on the Rodent Malaria Plasmodium chabaudi

Malaria vaccine developers are concerned that antigenic escape will erode vaccine efficacy. Evolutionary theorists have raised the possibility that some types of vaccine could also create conditions favoring the evolution of more virulent pathogens. Such evolution would put unvaccinated people at greater risk of severe disease. Here we test the impact of vaccination with a single highly purified antigen on the malaria parasite Plasmodium chabaudi evolving in laboratory mice. The antigen we used, AMA-1, is a component of several candidate malaria vaccines currently in various stages of trials in humans. We first found that a more virulent clone was less readily controlled by AMA-1-induced immunity than its less virulent progenitor. Replicated parasites were then serially passaged through control or AMA-1 vaccinated mice and evaluated after 10 and 21 rounds of selection. We found no evidence of evolution at the ama-1 locus. Instead, virulence evolved; AMA-1-selected parasites induced greater anemia in naïve mice than both control and ancestral parasites. Our data suggest that recombinant blood stage malaria vaccines can drive the evolution of more virulent malaria parasites.     

Platform for Plasmodium vivax vaccine discovery and development

Plasmodium vivax is the most prevalent malaria parasite on the American continent. It generates a global burden of 80-100 million cases annually and represents a tremendous public health problem, particularly in the American and Asian continents. A malaria vaccine would be considered the most cost-effective measure against this vector-borne disease and it would contribute to a reduction in malaria cases and to eventual eradication. Although significant progress has been achieved in the search for Plasmodium falciparum antigens that could be used in a vaccine, limited progress has been made in the search for P. vivax components that might be eligible for vaccine development. This is primarily due to the lack of in vitro cultures to serve as an antigen source and to inadequate funding. While the most advanced P. falciparum vaccine candidate is currently being tested in Phase III trials in Africa, the most advanced P. vivax candidates have only advanced to Phase I trials. Herein, we describe the overall strategy and progress in P. vivax vaccine research, from antigen discovery to preclinical and clinical development and we discuss the regional potential of Latin America to develop a comprehensive platform for vaccine development.     

A sticky situation: the unexpected stability of malaria elimination

Malaria eradication involves eliminating malaria from every country where transmission occurs. Current theory suggests that the post-elimination challenges of remaining malaria-free by stopping transmission from imported malaria will have onerous operational and financial requirements. Although resurgent malaria has occurred in a majority of countries that tried but failed to eliminate malaria, a review of resurgence in countries that successfully eliminated finds only four such failures out of 50 successful programmes. Data documenting malaria importation and onwards transmission in these countries suggests malaria transmission potential has declined by more than 50-fold (i.e. more than 98%) since before elimination. These outcomes suggest that elimination is a surprisingly stable state. Elimination''s ‘stickiness’ must be explained either by eliminating countries starting off qualitatively different from non-eliminating countries or becoming different once elimination was achieved. Countries that successfully eliminated were wealthier and had lower baseline endemicity than those that were unsuccessful, but our analysis shows that those same variables were at best incomplete predictors of the patterns of resurgence. Stability is reinforced by the loss of immunity to disease and by the health system''s increasing capacity to control malaria transmission after elimination through routine treatment of cases with antimalarial drugs supplemented by malaria outbreak control. Human travel patterns reinforce these patterns; as malaria recedes, fewer people carry malaria from remote endemic areas to remote areas where transmission potential remains high. Establishment of an international resource with backup capacity to control large outbreaks can make elimination stickier, increase the incentives for countries to eliminate, and ensure steady progress towards global eradication. Although available evidence supports malaria elimination''s stickiness at moderate-to-low transmission in areas with well-developed health systems, it is not yet clear if such patterns will hold in all areas. The sticky endpoint changes the projected costs of maintaining elimination and makes it substantially more attractive for countries acting alone, and it makes spatially progressive elimination a sensible strategy for a malaria eradication endgame.     

Control malaria to help defeat poverty, says WHO

In a report by the WHO, interventions against malaria could help alleviate poverty in countries where the disease is rife, and aid in boosting economic growth. The WHO calls on the international community, private foundations, and international agencies to commit funds for malaria interventions and research. This call was made since malaria has long term effects on trade, tourism, foreign investment, and commerce. Moreover, repeated bouts of malaria add to costs through malnutrition and death among children and time off work among adults. In this light, WHO further suggests the setting up of a malaria vaccine and purchase fund to spur pharmaceutical and biotechnological companies into developing a vaccine. Furthermore, new therapeutic, preventive and diagnostic tools need to be developed, particularly drugs, insecticides and dipstick tests.     

Plasmodium vivax pre-erythrocytic vaccines

An estimated 229 million cases of malaria occurred worldwide in 2019. Both, Plasmodium falciparum and P. vivax are responsible for most of the malaria disease burden in the world. Despite difficulties in obtaining an accurate number, the global estimates of cases in 2019 are approximately 229 million of which 2.8% are due to P. vivax, and the total number of malaria deaths are approximately 409 million. Regional elimination or global eradication of malaria will be a difficult task, particularly for P. vivax due to the particular biological features related to the hypnozoite, leading to relapse. Countries that have shown successful episodes of a decrease in P. falciparum malaria, are left with remaining P. vivax malaria cases. This is caused by the mechanism that the parasite has evolved to remain dormant in the liver forming hypnozoites. Furthermore, while clinical trials of vaccines against P. falciparum are making fast progress, a very different picture is seen with P. vivax, where only few candidates are currently active in clinical trials. We discuss the challenge that represent the hypnozoite for P. vivax vaccine development, the potential of Controlled Human Malaria Challenges (CHMI) and the leading vaccine candidates assessed in clinical trials.     

The PAL+ program, an incentive concerted action about malaria and associated infectious diseases, for developing countries

The French Ministry in charge of Research has launched a multi-institutional incentive concerted action to assist Southern countries on malaria: the PAL+ program. PAL+ aims at bringing out: 1) conditions to promote novel preventive and therapeutic tools adapted to existing situations in the countries concerned; 2) a contribution to help research teams in Southern countries become competitive. PAL+ plans to strengthen cooperative relationships with developing countries (subsaharian Africa, South East Asia and South American countries). Research programs were oriented towards public health needs in malaria-endemic countries and thus mainly focused on: i) development of new antimalarial drugs and new therapeutical strategies: new targets and new leads for drugs, clinical assays for recognition of malaria and optimization of effective treatment or prophylactic drug dosage; ii) pathophysiology of severe malaria: mechanisms of immunity, biology and genome of host and parasite and research leading to vaccine trials; iii) basic and field research on mosquito genetics and biology which may lead to new prevention and control opportunities; iv) social studies on behaviours and habits around prevention and medication of malaria. The objective is to help Southern countries increase their capacity in clinical research, epidemiology, therapeutics, public health and social science (e.g. behaviours and habits accompanying medicine-taking). This means a true partnership and training adapted to specific needs and based on sound science. Research was therefore largely pursued in the laboratories of Southern countries and PAL+ supported the initiative in different ways by: i) providing easier opportunities for scientists from the North to collaborate with scientists from the South; ii) supporting networks of scientist collaborations. This was achieved by setting up a new type of relationships between scientists, based on a continuous dialogue and on bringing them together in small meetings on thematic discussions, the so-called Ateliers de PAL+. The Ateliers should play a major role in increasing the scientific capacity in developing countries. PAL+ program is a commitment to speed up better understanding of the disease by helping endemic countries contribute to research for their own benefit.     

The prospects for a human malaria vaccine

Traditional methods of controlling malaria with insecticides and parasiticides have been inadequate. The use of hybridoma and recombinant DNA technologies to study the malaria parasite has permitted the identification of several antigens which may elicit protective immune responses. Clincial trials have begun to evaluate the merits of these molecules as vaccine candidates. It is hoped that their large scale production in genetically engineered hosts will result in the development of an effective vaccine.     

Malaria vaccines: triumphs or tribulations?

A safe and effective malaria vaccine will greatly facilitate efforts to control the global spread of malaria. This paper discusses the conceptual framework for developing malaria vaccines and some of the difficulties that the various approaches face. It emphasizes the role of pre-erythrocytic malaria vaccines, which are designed to protect against malaria infection, rather than simply prevent clinical disease. It describes recent encouraging results in human subjects with the RTS,S vaccine, a promising pre-erythrocytic malaria vaccine candidate.     

Synergism/complementarity of recombinant adenoviral vectors and other vaccination platforms during induction of protective immunity against malaria

The lack of immunogenicity of most malaria antigens and the complex immune responses required for achieving protective immunity against this infectious disease have traditionally hampered the development of an efficient human malaria vaccine. The current boom in development of recombinant viral vectors and their use in prime-boost protocols that result in enhanced immune outcomes have increased the number of malaria vaccine candidates that access pre-clinical and clinical trials. In the frontline, adenoviruses and poxviruses seem to be giving the best immunization results in experimental animals and their mutual combination, or their combination with recombinant proteins (formulated in adjuvants and given in sequence or being given as protein/virus admixtures), has been shown to reach unprecedented levels of anti-malaria immunity that predictably will be somehow reproduced in the human setting. However, all this optimism was previously seen in the malaria vaccine development field without many real applicable results to date. We describe here the current state-of-the-art in the field of recombinant adenovirus research for malaria vaccine development, in particular referring to their use in combination with other immunogens in heterologous prime-boost protocols, while trying to simultaneously show our contributions and point of view on this subject.     

Estimated impact of RTS,S/AS01 malaria vaccine allocation strategies in sub-Saharan Africa: A modelling study

BackgroundThe RTS,S/AS01 vaccine against Plasmodium falciparum malaria infection completed phase III trials in 2014 and demonstrated efficacy against clinical malaria of approximately 36% over 4 years for a 4-dose schedule in children aged 5–17 months. Pilot vaccine implementation has recently begun in 3 African countries. If the pilots demonstrate both a positive health impact and resolve remaining safety concerns, wider roll-out could be recommended from 2021 onwards. Vaccine demand may, however, outstrip initial supply. We sought to identify where vaccine introduction should be prioritised to maximise public health impact under a range of supply constraints using mathematical modelling.Methods and findingsUsing a mathematical model of P. falciparum malaria transmission and RTS,S vaccine impact, we estimated the clinical cases and deaths averted in children aged 0–5 years in sub-Saharan Africa under 2 scenarios for vaccine coverage (100% and realistic) and 2 scenarios for other interventions (current coverage and World Health Organization [WHO] Global Technical Strategy targets). We used a prioritisation algorithm to identify potential allocative efficiency gains from prioritising vaccine allocation among countries or administrative units to maximise cases or deaths averted. If malaria burden at introduction is similar to current levels—assuming realistic vaccine coverage and country-level prioritisation in areas with parasite prevalence >10%—we estimate that 4.3 million malaria cases (95% credible interval [CrI] 2.8–6.8 million) and 22,000 deaths (95% CrI 11,000–35,000) in children younger than 5 years could be averted annually at a dose constraint of 30 million. This decreases to 3.0 million cases (95% CrI 2.0–4.7 million) and 14,000 deaths (95% CrI 7,000–23,000) at a dose constraint of 20 million, and increases to 6.6 million cases (95% CrI 4.2–10.8 million) and 38,000 deaths (95% CrI 18,000–61,000) at a dose constraint of 60 million. At 100% vaccine coverage, these impact estimates increase to 5.2 million cases (95% CrI 3.5–8.2 million) and 27,000 deaths (95% CrI 14,000–43,000), 3.9 million cases (95% CrI 2.7–6.0 million) and 19,000 deaths (95% CrI 10,000–30,000), and 10.0 million cases (95% CrI 6.7–15.7 million) and 51,000 deaths (95% CrI 25,000–82,000), respectively. Under realistic vaccine coverage, if the vaccine is prioritised sub-nationally, 5.3 million cases (95% CrI 3.5–8.2 million) and 24,000 deaths (95% CrI 12,000–38,000) could be averted at a dose constraint of 30 million. Furthermore, sub-national prioritisation would allow introduction in almost double the number of countries compared to national prioritisation (21 versus 11). If vaccine introduction is prioritised in the 3 pilot countries (Ghana, Kenya, and Malawi), health impact would be reduced, but this effect becomes less substantial (change of <5%) if 50 million or more doses are available. We did not account for within-country variation in vaccine coverage, and the optimisation was based on a single outcome measure, therefore this study should be used to understand overall trends rather than guide country-specific allocation.ConclusionsThese results suggest that the impact of constraints in vaccine supply on the public health impact of the RTS,S malaria vaccine could be reduced by introducing the vaccine at the sub-national level and prioritising countries with the highest malaria incidence.

Alexandra Hogan and colleagues explore strategies to optimize vaccine allocation for maximum public health benefit in the face of potential supply constraints.     

HIV vaccines: a global perspective

Twenty years after its recognition, HIV/AIDS has become the most important infectious disease globally and the leading cause of death in Africa. A preventive vaccine represents the best long-term hope for its control. The development of such a vaccine, however, has encountered a number of scientific challenges, including the lack of information on immune correlates of protection, the limitations in our understanding of the relevance of primate protection experiments in relation to vaccine-induced protection in humans, and the significance of genetic and immunologic variability of HIV strains for potential vaccine efficacy. Despite these uncertainties, the first phase I trial of an HIV vaccine was conducted in the United States in 1987. Since then more than 30 candidate vaccines have been tested in over 70 phase I/II clinical trials in both industrialized and developing countries. The first HIV vaccine trial in a developing country was conducted in 1993, six years after the first trial in the United States. Since then eighteen phase I/II trials and one phase III trial have been or are being conducted in developing countries, and additional phase II and III trials are planned to start in 2003. Most of these initial trials have been conducted in Thailand, but more recently trials have been initiated in Africa, Latin America and the Caribbean. Over the past years, the HIV vaccine development effort has followed three major overlapping paradigms. The first "wave" of candidate vaccines aimed at inducing neutralizing antibodies. The second wave focused on stimulation of CD8+ T-cell responses. The current "wave" of HIV vaccine research is aimed at optimizing both humoral and cell-mediated immune responses. The first generation of candidate vaccines (based on the HIV envelope protein) entered phase III efficacy evaluation in 1998, and definitive results from these trials will become available in 2003. Plans to ensure wide access to future HIV vaccines must be developed well in advance.     

The London School of Hygiene and Tropical Medicine: a new century of malaria research

The global malaria situation has scarcely improved in the last 100 years, despite major advances in our knowledge of the basic biology, epidemiology and clinical basis of the disease. Effective malaria control, leading to a significant decrease in the morbidity and mortality attributable to malaria, will require a multidisciplinary approach. New tools--drugs, vaccine and insecticides--are needed but there is also much to be gained by better use of existing tools: using drugs in combination in order to slow the development of drug resistance; targeting resources to areas of greatest need; using geographic information systems to map the populations at risk and more sophisticated marketing techniques to distribute bed nets and insecticides. Sustainable malaria control may require the deployment of a highly effective vaccine, but there is much that can be done in the meantime to reduce the burden of disease.     

An update on the search for a Plasmodium vivax vaccine

Although Plasmodium falciparum is the leading cause of morbidity and mortality due to malaria worldwide, nearly 2.5 billion people, mostly outside Africa, are also at risk from malaria caused by Plasmodium vivax infection. Currently, almost all efforts to develop a malaria vaccine have focused on P. falciparum. For example, there are 23 P. falciparum vaccine candidates undergoing advanced clinical studies and only two P. vivax vaccine candidates being tested in preliminary (Phase I) clinical trials, with few others being assessed in preclinical studies. More investment and a greater effort toward the development of P. vivax vaccine components for a multi-species vaccine are required. This is mainly because of the wide geographical coexistence of both parasite species but also because of increasing drug resistance, recent observations of severe and lethal P. vivax cases and relapsing parasite behaviour. Availability of the P. vivax genome has contributed to antigen discovery but new means to test vaccines in future trials remain to be designed.