Introduction

Malaria is caused by two main species of parasites: ​P falciparum​ and P​ vivax​. Malaria is
transmitted through the bites of female Anopheles mosquitoes,​ Plasmodium​ sporozoites are
inoculated into the human host which migrate to the liver where they infect hepatic cells and
mature into schizonts. Rupture of schizonts releases merozoites which invade erythrocytes.
These blood stage parasite are responsible for extensive malaria pathology and are a current
target for vaccine development. The different parasite stages and numerous immune evasion
strategies malaria employs including a higher rate of polymorphism for most vaccine candidate
antigens has extended the search for a malaria vaccine well past expectations. However, the
empirical approach developing a vaccine that provides sterilising immunity similar to that of the
smallpox vaccine is incredibly difficult. This imperfect vaccine provides an alternative to the
traditional approach to vaccines without achieving sterilising immunity.

Anti-disease vaccines can be defined as vaccines that reduce clinical symptoms and mortality
without altering the parasite count; alleviating malaria’s debilitating symptoms including cerebral
malaria, anemia and fever among other pathological manifestations.. Anti-disease vaccines
would work similarly to the anti-disease immunity naturally acquired. It seems that parasitaemia
can be unrelated to the disease severity; those protected are asymptomatic yet have a high
parasite burden whereas those without protection have low parasite levels but display severe
clinical manifestations. This natural immunity gives credit to the feasibility of an anti-disease
vaccine. Anti-disease vaccines aim to confer similar protection as naturally acquired
anti-disease immunity, where the main goal is not to reduce parasitaemia but to avoid the
severe clinical consequences of the disease.

The anti-toxic approach and the anti-GPI vaccine

Anti-disease vaccine can focus on counteracting the toxins produced during disease, this was
first pioneered when formulating the tetanus and diphtheria vaccines. Evidence suggests
malaria pathology arises when parasitic toxins elicit a proinflammatory cytokine response, which
upregulates endothelial cell adhesion molecules (CAMS) and stimulates the production of
Tumor Necrosis Factor-alpha (TNF-a) and IL-1 (interleukin). These factors are associated with
clinical symptoms; peak TNF-a release is synchronised with the schizont rupture and fever
episodes. Indicating there is malarial ‘toxin’, any toxin by definition is required to cause
pathogenesis of a disease and at high dosage, fatality. Glycosylphosphatidylinositol (GPI) is the
proposed malaria toxin. GPI is a phospholipid found as components of transmembrane anchor
proteins or as soluble exoantigens secreted during infections. This is supported by studies,
wherein mice immunised with modified GPI-exoantigens gained increased protection to clinical
disease, viathis was associated with blocking of TNF-induction by IgM by binding to GPI
stimulating a T-independent mechanism compared to naive control mice (Bates and
Kwiatkowski 1994). This suggests that GPI antibodies provide anti-disease immunity by
inhibiting TNF-a induction. Additionally, it has been found that the immune response to GPI
involves a transient IgG3 response (Boutlis et al, 2003.) Therefore, any anti-GPI vaccine must
overcome the issue of stimulating a lasting immunological response otherwise the benefits are
fleeting. This illustrates one of the main issues that has been plaguing the development of a
malaria vaccine; definitive knowledge about the immune response during infection and how
acquired immunity is achieved is lacking. Uncertainty surrounding the immune response to GPI
will complicate the search for a vaccine that achieves immunological memory to repeat
exposure. Problems not just anti-disease vaccines have faced illustrating the need for further
research to elucidate the immune response.

Schofield et al (2002) found that mice immunised with a chemical synthesised version of P.
falciparum GPI glycan displayed less severe symptoms of malaria when exposed to infection
than controls, acquiring protection against cerebral malaria syndrome, malarial acidosis, fatality
and other pathologies of the disease. This indicates that anti-GPI antibody production
neutralises the proinflammatory cytokine activity linked to pathogenesis. Schofield et al (2002)
concludes that GPI therefore confirming it to be a significant “endotoxin of parasitic origin”,
providing evidence that GPI fulfils the requirements of a toxin.

Evaluation of the Anti-GPI Vaccine

An advantage of the anti-GPI approach is evidence supports its feasibility to provide to combat
malaria pathogenesis.​ ​GPI-specific protective immunity has gained support from a longitudinal
cohort study performed by Naik R S et al, 2000. Naik analysed the anti-GPI antibody response
in endemic areas, finding that these individuals gained protection through a parasite
GPI-specific IgG response. This supports the role GPI plays in acquiring tolerance to malaria
therefore, an anti-GPI vaccine may be a promising way to confer neutralising immunity.
Another advantage of an anti-GPI vaccine is that it could work for multiple species of
Plasmodium​ that cause malaria. GPI performs vital functions for plasmodium protozoa;
necessary for survival and development. GPI is highly conserved across species (Tachado, S.D,
1997. Schofield et al, 2002), this makes an anti-GPI vaccine ideal as it could possibly affect
multiple strains of malaria infection. GPIs important role for parasite survival also makes
vaccine-induced selection unlikely, so anti-GPI vaccines should remain protective unlike typical
vaccines where strains can become resistant like in the case of polio and hepatitis.

One flaw of the anti-GPI vaccine, is that complete relief from pathology is unlikely; other less
studied toxins may have equal impact on pathology. Hemozoin, a metabolic by product of
haemoglobin breakdown during infection. Evidence shows that hemozoin has immunogenic
properties stimulating the same TLR9 receptor GPI activates and release similar cytokines
(Coban et al 2010.) This illustrates that other toxins have pathological effects that an anti-GPI
vaccine cannot protect against. Furthermore, neutralising toxins cannot cancel the effects of
immunogenic antigens. Surface antigens like PfEMP1 and AMP-1 incur sequestration and
rosetting, contributing to anaemia and cerebral malaria. Therefore, an anti-toxic vaccine may
only offers partial anti-disease protection.
Evaluation of the Anti-Disease Approach

The anti-disease vaccine is especially beneficial within holoendemic regions, where they could
substantially lower mortality and morbidity improving the quality of life for sufferers within
endemic countries. This is becoming increasingly important with the onset of malaria drug
resistance, therefore, anti-disease vaccines could provide effective treatment.
However, problems arise from treating symptoms rather lowering the parasite burden as
it increases the general prevalence of parasites within the population as transmission continues.
While this alone would make naive individuals more likely to encounter infection, they may also
contract more severe infections. Studies of the consequences of anti-disease vaccines on
parasite prevalence, transmission rates and virulence, show that the long-term effects could
cancel the short-term relief provided (Gandon et al, 2001. Mackinnon et al, 2008.) Generally
virulent pathogens kill the host before they can be transmitted. This selects against virulent
pathogens. Imperfect vaccines allow unchecked parasites growth while the host remains
asymptomatic. This dampens selection against virulent pathogens, as the host continues to
survive and leaves the infection untreated. Therefore, strains of malaria with a high intrinsic
virulence (more severe for naive individuals) pose grave risks for unvaccinated individuals. This
creates an ethical question of whether the anti-disease vaccines should be used to alleviate the
debilitating effects within endemic countries at the risk of the unvaccinated individuals.
MacKinnon et al, (2008) suggest combining an anti-disease vaccine with vaccines that block
transmission to help lower the influx of more virulent pathogens into the general population.
Therefore, caution should be exerted implementing anti-disease vaccine programmes as the
evolution of increased intrinsic virulence exceeds the duration of clinical trial and may be
unnoticed.

Conclusion

Anti-disease vaccines could aid the development of an effective malaria vaccine; the anti-GPI
vaccine combined with other typical anti-parasite vaccines could provide a multi-faceted
protection against malaria. Despite the threat of increased virulence to unvaccinated individuals
an anti-disease vaccine could be successfully utilised regardless. Greenwood (2009) questions
the value of a malaria vaccine unless alongside existing vector control programmes and
preventative methods instated have greatly reduced the total mortality and morbidity of Malaria.
A combined effort of vaccine implementation supported by existing transmission control
framework could help eliminate malaria in areas by mitigating the adverse effects of an
increased parasite burden if we relied on an anti disease vaccine alone.

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