A probabilistic model of pre-erythrocytic malaria vaccine combination in mice

Abstract

Malaria remains one the world’s most deadly infectious diseases, with almost half a million deaths and over 150 million clinical cases each year. An effective vaccine would contribute enormously to malaria control and will almost certainly be required for eventual eradication of the disease. However, the leading malaria vaccine candidate, RTS,S, shows only 30–50% efficacy under field conditions, making it less cost-effective than long-lasting insecticide treated bed nets. Other subunit malaria vaccine candidates, including TRAP-based vaccines, show no better protective efficacy. This has led to increased interest in combining subunit malaria vaccines as a means of enhancing protective efficacy. Mathematical models of the effect of combining such vaccines on protective efficacy can help inform optimal vaccine strategies and decision-making at all stages of the clinical process. So far, however, no such model has been developed for pre-clinical murine studies, the stage at which all candidate antigens and combinations begin evaluation. To address this gap, this paper develops a mathematical model of vaccine combination adapted to murine malaria studies. The model is based on simple probabilistic assumptions which put the model on a firmer theoretical footing than previous clinical models, which rather than deriving a relationship between immune responses and protective efficacy posit the relationship to be either exponential or Hill curves. Data from pre-clinical murine malaria studies are used to derive values for unknowns in the model which in turn allows simulations of vaccine combination efficacy and suggests optimal strategies to pursue. Finally, the ability of the model to shed light on fundamental biological variables of murine malaria such as the blood stage growth rate and sporozoite infectivity is explored.

Discovery of four new B-cell protective epitopes for malaria using Q beta virus-like particle as platform

“…Though none of the peptide vaccines in this study shows high levels of protection, the utility of these approaches will be in quickly and reliably discovering new protective B-cell epitopes susceptible to further improvement as parts of highly protective vaccines. The sensitivity of the platform to even low levels of protective efficacy is well-established 11 , and is an advantage of the approach, although variations in (for instance) parasite infectivity between challenge experiments means direct comparison between different experiments is often not possible 20 . The Qβ-peptide platform is also of use for pre-clinical screening of epitopes that will be co-dominant, avoiding antigenic interference, a problem likely to be of increasing importance as single subunit vaccines are replaced by more complex combination strategies 20 – 22 .…”

A VLP for validation of the Plasmodium falciparum circumsporozoite protein junctional epitope for vaccine development

“…In theory, two vaccines generating immune responses against different targets will, if either is weakly protective alone, show markedly enhanced efficacy when combined 12 . To test whether “ADGN long” represents a truly novel epitope, rather than its effects being mediated through anti-NANP antibodies as with Qβ-(NANP) 6 , an experiment was carried out combining Qβ-(ADGN long) and Qβ-(NANP) 6 vaccines under suboptimal conditions, with dosage reduced compared to previous experiments (Fig.…”

“…To further test whether the enhancement in protective efficacy was consistent with theoretical predictions, a mathematical model developed by our group 12 was adapted to present purposes. From that mathematical model, the following expression can be derived where L V and L N are the numbers of infected hepatocytes in vaccinated and naïve mice, respectively; i V 1 and i V 2 are the reductions in infectivity caused by two different immune components (in this case, against (NANP) 6 and ADGN-long); g is the blood-stage growth rate (calculated in ref.…”

“…Although the immunogenicity of short peptides is enhanced by coupling them to virus-like particles (VLPs) 9 , the aim of this paper is not necessarily to advocate VLP-peptide vaccines for clinical use, nor is the aim to obtain high levels of protective efficacy against challenge; one of the main metrics of vaccine efficacy used here is a delay in time to reach 1% blood-stage parasitaemia, previously validated 10 , 11 and in fact a more sensitive metric to use when testing the hypothesis that combining vaccines enhances efficacy since sterile protection represents saturation 12 . Rather, the focus of this paper is to explore the potential of VLP-peptide vaccines in pre-clinical screening of epitopes for potential protective efficacy and to answer other basic questions useful to malaria vaccine development.…”

Protective efficacy of peptides from Plasmodium vivax circumsporozoite protein

“…In that study soluble full-length P. vivax circumsporozoite protein (PvCSP) was used to vaccinate human volunteers. Low levels of protective efficacy were seen, prompting exploration of alternative strategies [5] , [6] , [7] , [8] . The present study uses a virus-like particle, Qβ, as a platform for eliciting strong antibody responses against PvCSP peptides, followed by challenge of vaccinated mice with transgenic P. berghei parasites expressing the homologous PvCSP protein.…”