In 2016, malaria caused an estimated 216 million illnesses and 445,000 confirmed deaths globally. The disease is caused by a parasite, and mosquitos infected with the parasite transmit them to humans when they bite. In humans, the parasites enter the body and head to the liver before spending part of their life cycle in red blood cells, which cause the symptoms of the disease.

Prevention efforts have reduced the burden of malaria but eliminating the disease will require new tools. One option is to use vaccines. The world’s first malaria vaccine – a so-called pre-erythrocytic vaccine (PEV) – targets the stages preceding the parasite reaching the liver. This vaccine prevents malaria parasites from infecting people, but it is only partially effective. Scientists are also developing transmission-blocking vaccines (TBVs). These TBVs block the development of malaria parasites in mosquitos that bite vaccinated humans. So far, the most promising TBV candidates are also only partly effective.

It is possible that using PEV and TBV vaccines together could boost their effectiveness, since the TBV vaccines reduce the number of parasites that infect each mosquito. This means that fewer parasites are injected into the next person. Currently, the PEVs work better when there are fewer parasites infecting a person.

Now, Sherrard-Smith et al. show that combining TBVs with PEVs enhances their antimalarial effects. In the experiments, Sherrard-Smith et al. treated mice with either TBV or PEV vaccines, or both. Then, the mice were exposed to mosquitos infected with the malaria parasite. As expected, the TBV and PEV treatments were only partially effective when used alone. But exposing the mice to both TBVs and PEVs eliminated the parasites from the mosquitos and the mice.

The combined benefit of TBVs and PEVs were greater than would be expected if either vaccine was acting alone and the effects were simply multiplied, suggesting they enhance each other’s effects. More studies of TBVs in humans are needed to prove they are safe and effective in the real world. More studies also are needed to confirm what Sherrard-Smith et al. found in mice would happen in humans treated with a combination of TBV and PEV vaccines. But if such future studies prove this combination approach is effective, it could be a powerful tool in the fight against malaria.

Malaria remains a major global health challenge with an estimated 216 million new cases and 445,000 deaths in 2016 (World Health Organization, 2017). Whilst current tools have substantially reduced the global burden of disease, new tools will be needed to achieve malaria elimination (Walker et al., 2016). Early development of malaria vaccines focused on either the pre-erythrocytic stage vaccine (PEV) – eliciting an immune response to prevent incoming sporozoites from establishing patent infection – or blood-stage – boosting natural responses to surface proteins on the infected erythrocytes (Schwartz et al., 2012). The first malaria vaccine RTS,S/AS01 to complete Phase III trials is a PEV vaccine and has been demonstrated to be partially effective, reducing clinical incidence in 5 – 17-month-old children by 36.3% (95%CI: 31.8 – 40.5%) over 40 months follow-up (RTSS Clinical Trials Partnership, 2015). Further candidate PEV vaccines include those that achieve protective immunity through irradiated/chemo-attenuated Plasmodium falciparum sporozoites, (e.g. PfSPZ vaccines [Seder et al., 2013]), those that use viral vectors to induce T-cell responses to provide protection (de Barra et al., 2014; MVVC group et al., 2015) and the promising next-generation RTS,S-like vaccine, R21 (Collins et al., 2017). A range of vaccines that target human-to-mosquito transmission by attacking sexual, sporogonic, and/or mosquito antigens (transmission-blocking vaccines, TBV) are also under development (Talaat et al., 2016; Wu et al., 2008). Pre-clinical investigations have identified multiple antigens (e.g. Pfs25, P230, P48/45) as targets for TBV candidates that, when administered, can reduce transmission to mosquitoes (Hoffman et al., 2015; Sauerwein and Richie, 2015), but complete, or reproducible, translation to the clinic has not been achieved so far (Talaat et al., 2016; Hoffman et al., 2015; Sauerwein and Richie, 2015).

One of the major challenges encountered in developing PEV malaria vaccines is the partial protection achieved against each exposure, despite high levels of induced antibody titres. It has been hypothesized that this may be in part due to the over-dispersed distribution of sporozoites in each infectious bite, such that despite inducing a high per-parasite killing efficacy, the probability that at least one parasite reaches the liver and progresses to blood-stage infection remains high (White et al., 2013; Bejon et al., 2005). The classical approach to overcoming this is to attempt to further increase either the quantity, breadth or quality of the immune response (Remarque et al., 2012; Courtin et al., 2009; Chaudhury et al., 2016). We hypothesized that an alternative mechanism would be to combine a PEV with approaches that reduce the number of sporozoites in the mosquito salivary glands. TBVs have been demonstrated to act in this way, reducing ookinete and sporozoite density (Bompard et al., 2017; Blagborough et al., 2013). We sought therefore to identify whether this mechanism could result in synergistic interactions between PEVs and TBVs co-administered within a population.

To test this hypothesis, we used an established murine population assay to investigate the clearance of malaria over multiple generations in a controlled laboratory environment (Blagborough et al., 2013). Here, the rodent malaria parasite Plasmodium berghei is passed between populations of mice by the direct feeding of Anopheles stephensi mosquitoes. To simulate the antibody response to a PEV, a monoclonal antibody (mAb-3D11) - which targets the same corresponding parasite circumsporozoite protein (CSP) as RTS,S – was passively transferred (intravenously) into mice. To act as a partially effective PEV (broadly comparable to RTS,S), a mAb-3D11 dose was selected which reduces mosquito-to-mouse transmission probability by ~50% (as evaluated in naive mouse populations, transfused with differing doses of 3D11, challenged with five mosquito bites, see Materials and methods). Sterilizing immunity of 47.2% was titrated over multiple challenges. The complementary actions of a TBV antibody response were simulated using an anti-Pfs25 monoclonal antibody 4B7 (mAb-4B7), administered by passive transfer, which targets the same parasite stages as the most currently advanced human TBV candidate, Pfs25 (Talaat et al., 2016). This well-established transmission-blocking monoclonal antibody was used in combination with a transgenic P. berghei (PbPfs25DR3) parasite that expresses Pfs25 in place of its rodent homologue. PbPfs25DR3 is phenotypically indistinguishable to WT P. berghei, expresses Pfs25 on the surface of the zygote/ookinete, and has been used previously to assay a range of TBVs (Goodman et al., 2011; Kapulu et al., 2015). A series of transfused mAb-4B7 doses were tested in multiple (n = 6) direct feeding assays to titrate the appropriate doses to generate a 50%, 65% and 85% reduction in transmission to the mosquito (measured as reduction in oocyst prevalence) (see Materials and methods).

We undertook a series of experiments with either PEV alone, TBV alone at three different efficacies (50%, 65% and 85%), or combinations of the two across four generations of transmission. For each experiment mice were exposed to either 1, 2, 5 or 10 infectious mosquito bites to allow estimation of combined transmission-blocking efficacies between 20% and 100% (Materials and methods).

At lower TBV antibody dose exposure levels (50% and 65%), the probability of eliminating all parasites from the mouse/mosquito populations was greater when PEV and TBV antibodies were administered together compared to singly, irrespective of the dose of the TBV antibody administered (Figure 1). Using statistical methods that explicitly capture parasite density and account for the impact of the interventions on both the prevalence and density of infection (Sherrard-Smith et al., 2017), we estimated PEV antibody alone to reduce the prevalence of infection by 48.0% (95% credible interval, CrI, 36.6–58.0%). Similarly, use of TBV antibody alone reduced the prevalence of infection by 33.9% (95% CrI: 18.2–47.4%), 74.3% (65.7%–82.4%) and 95.8% (90.2%–100%) for the 50%, 65% and 85% individual efficacy titres, respectively. If the actions of the two antibody types were to act independently, the predicted combined efficacy would be 83.3% (79.1–87.0%). A substantially higher efficacy of 90.8% (86.7–94.2%) (p=0.0035) was observed in the PEV +TBV antibody group, indicating a synergistic interaction (Table 1). Here, the 95% Credible Intervals did not overlap the median estimates, demonstrating a significant difference between the two treatments. The same relationship was observed when examining vaccine efficacy against parasite density (p=0.0025) (Table 1).

Figure 1 with 1 supplement see all

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Sub-dividing the data by TBV antibody dose, the greatest synergistic enhancement in efficacy against parasite prevalence was seen at lower doses of functional TBV antibodies (Figure 2). A TBV antibody dose which reduces mouse-to-mosquito transmission by 50% increased the efficacy of PEV antibody prevalence to 82.2% (74.6–88.9%) compared to an expected 65% (57.7–73.2%) efficacy if the vaccines acted independently, a strong indication of synergy (p=0.0015). Similar synergistic effects against parasite density were observed (Figure 2, p <0.0001). Weaker synergistic effects were observed against parasite prevalence and density for the PEV +TBV antibody at the 65% dose (Figure 2, p=0.0675, 0.02, respectively) (Table 1). At the highest TBV antibody dose (85%), the TBV alone already reduced parasites in the population to low levels, hence there was insufficient power to detect further synergy between the interventions as all parasites were eliminated from the experimental population (Figure 1).

Figure 2

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The impact of circulating TBV antibody on the reduction of parasites within the mosquito explains the greater efficacy of the PEV antibody in the combination treatment groups. The presence of TBV antibody (mAb-4B7) reduced oocyst counts in infected mosquitoes (ANOVA: F_1,1525 = 75.3, p<0.0001). Similarly, TBV antibody presence reduced sporozoite density in infected mosquitoes (ANOVA: F_1,707 = 163.9, p<0.0001). Figure 3A,B and C further illustrate the effect that TBVs have on sporozoite density distribution for the TBV-50%, 65% and 85% single treatment groups respectively. At each dose, the tail of the distribution of sporozoites is curtailed progressively across transmission cycles. Figure 3D illustrates that the efficacy of the PEV is density-dependent, with higher efficacy achieved when mosquitoes have lower sporozoite density.

Figure 3

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The efficacy of multiple PEV and TBV candidates against rodent and human parasites have been shown to depend on parasite density; TBV (anti-Pfs25, anti-Pfs48/45 and immune blocking serum) efficacy decreases with increased parasite dose (Churcher et al., 2012; Miura et al., 2016) and a representative PEV (RTS,S) only provides sterilizing immunity in volunteers against lightly infected mosquitoes (Churcher et al., 2017). This suggests that both types of vaccine can halt transmission against a defined (but currently uncharacterized) quantity of parasites, which is enough to prevent onward infection in lightly infected mosquitoes/humans, but that onward transmission is still possible from heavily infected mosquitoes or individuals.

Here, a partially effective TBV antibody reduced the number of parasites in infected mosquitoes, ensuring that the PEV antibodies encounter fewer parasites than would otherwise be expected if only a single antibody/vaccine class was administered in isolation. Thus, the subsequently reduced parasite burden increased the efficacy of the PEV when co-administered with a TBV. Potentially, a synergistic response could be induced by an unspecified biochemical or immunological interaction between the two vaccines. This explanation can be discounted within this system as the experimental design results in mosquito-to-mouse transmission being measured prior to the administration of a transmission-blocking intervention (passive transfer of mAb-4B7 1 hr prior to blood feed) as a new, naive batch of mice were infected in each generation.

The greatest synergy was observed in the lower TBV dose group, although it is likely to operate across all TBV and PEV doses when vaccine reduces parasite density but fails to clear infection from host or vector. The 85% TBV dose administered alone eliminated the parasite over a single generation without the action of the PEV so there was no opportunity to show synergy. A 100% efficacious PEV or TBV would not require augmenting with an alternative vaccine, although their efficacy is still likely to drop over time as antibodies decay so combining highly effective vaccine may still be advantageous depending on the relative rates of antibody loss.

While the direct translatability of rodent experiments to human health is variable, this approach is invaluable to demonstrate unequivocally that the mechanism behind the observed synergy is the direct result of TBV antibody reducing parasite density in infected mice and thereby enabling the density-dependent PEV antibody to be optimal (Figure 3). This mechanism is very likely to mirror that for humans, which cannot be tested directly due to ethical considerations and complex environmental variation. Whilst the murine system uses P. berghei, the mechanism of action of the PEV antibodies administered is matched to the antibody-based mechanism of the RTS,S vaccine; that is sporozoite invasion of the liver is inhibited by the presence of CSP-targeted antibodies in mice both in vivo and ex vivo (Grüner et al., 2003). The P. berghei strain used here is genetically modified to express the human TBV candidate, P. falciparum P25 (Pfs25) in place of its P. berghei counterpart. Thus, a proven anti-falciparum TBV mAb (4B7) can be used directly within the model (Goodman et al., 2011). The evidence that co-administering TBV and PEV antibodies can accelerate toward controlling malaria transmission is a first step toward trialing such combinations in more natural parasite-vector-host combinations and environments. There is good reason to believe that the population dynamics of parasites and partially effective vaccines may be similar in human malaria. Transmission of human malaria from human-to-mosquito and mosquito-to-human is also considered to depend on the density of the parasite (Churcher et al., 2013; Sinden et al., 2007). The average number of oocysts in wild caught mosquitoes is likely to be substantially lower than the numbers observed in the rodent system (Rosenberg, 2008) but oocyst distribution is highly over-dispersed (Medley et al., 1993) meaning that some mosquitoes have very-high-density infections. These highly infected mosquitoes are likely to be more infectious, so reducing their frequency through adding a TBV, could have additional impact on overall transmission. The epidemiological importance of any synergistic interaction between vaccine types in the field is hard to predict and will depend on many confounding factors such as human immunity, drug treatment, vector susceptibility, antigen escape, amongst others. Transmission is likely to be highly heterogeneous, caused by factors such as vaccine non-responders and super-transmitting hosts. The impact of different types of heterogeneity can be investigated under controlled laboratory scenarios using the murine population assay, varying the vaccinated coverage, antibody dose and changing biting heterogeneity within a population. This could help understand the relative importance of these different heterogeneities and could be used to support the design of appropriately powered Phase III trials (or alternative trial designs) to fully assess the impact of combining vaccine components with alternative mechanisms of action.

There is no ‘magic bullet’ intervention against malaria and the current global strategy is to combine vector control and drug treatment tools in a timely manner to move towards malaria elimination. Our results suggest that the same approach might be taken for the use of vaccines and comprises the first practical demonstration that combining TBVs and PEVs may have auxiliary benefits. Synergism between PEV and TBVs could potentially enhance the efficacy of the current PEV vaccines, resulting in reduced burden and potentially elimination in areas where it was not previously possible. The development of novel anti-malarial vaccines is both costly and time-consuming. Combining partially effective vaccines of differing anti-parasitic classes may be therefore a pragmatic and powerful way to accelerate malaria elimination efforts. Synergism between PEV, TBVs and potentially a blood-stage vaccine (either administered separately or as a multi-component vaccine) could potentially enhance the efficacy of single vaccines, resulting in reduced burden and potentially elimination in areas where it was not previously possible.

All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

1. Ellie Sherrard-Smith

   MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom

   Contribution

   Formal analysis, Validation, Investigation, Visualization, Methodology, Writing—original draft, Writing—review and editing

   Contributed equally with

   Katarzyna A Sala

   For correspondence

   e.sherrard-smith@imperial.ac.uk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8317-7992

2. Katarzyna A Sala

   Department of Life Sciences, Imperial College London, London, United Kingdom

   Contribution

   Data curation, Investigation, Methodology, Writing—review and editing

   Contributed equally with

   Ellie Sherrard-Smith

   Competing interests

   No competing interests declared

3. Michael Betancourt

   Applied Statistics Center, Columbia University, New York, United States

   Contribution

   Formal analysis, Validation, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-2900-0931

4. Leanna M Upton

   Department of Life Sciences, Imperial College London, London, United Kingdom

   Contribution

   Data curation, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

5. Fiona Angrisano

   Department of Life Sciences, Imperial College London, London, United Kingdom

   Contribution

   Data curation, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-0457-5982

6. Merribeth J Morin

   PATH’s Malaria Vaccine Initiative, Washington, United States

   Contribution

   Conceptualization, Supervision, Project administration, Writing—review and editing

   Competing interests

   No competing interests declared

7. Azra C Ghani

   MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom

   Contribution

   Conceptualization, Supervision, Funding acquisition, Methodology, Writing—original draft, Project administration, Writing—review and editing

   Contributed equally with

   Thomas S Churcher and Andrew M Blagborough

   Competing interests

   No competing interests declared

8. Thomas S Churcher

   MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom

   Contribution

   Conceptualization, Supervision, Funding acquisition, Methodology, Writing—original draft, Project administration, Writing—review and editing

   Contributed equally with

   Azra C Ghani and Andrew M Blagborough

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-8442-0525

9. Andrew M Blagborough

   Department of Life Sciences, Imperial College London, London, United Kingdom

   Contribution

   Conceptualization, Data curation, Supervision, Funding acquisition, Methodology, Writing—original draft, Writing—review and editing

   Contributed equally with

   Azra C Ghani and Thomas S Churcher

   Competing interests

   No competing interests declared

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