Global malaria eradication and the importance of Plasmodium falciparum epidemiology in Africa

Malaria is a mosquito borne disease which, in humans, is caused by five protozoa:
Plasmodium falciparum, P. vivax, P. malariae, related sibling species of P. ovale, and P. knowlesi. P. vivax is the most cosmopolitan of the human malarias, reaching historical latitudinal extremes
of 64° north and 32° south 1]. The public health burden posed by P. vivax is no longer regarded as benign, causing severe morbidity and death 2]. Nevertheless, P. falciparum remains the single most important threat to public health at a global scale, accounting
for more than 90% of the world’s malaria mortality.

Forty thousand years on, P. falciparum remains entrenched in Africa, largely as a result of optimal environmental conditions
for the world’s most efficient Anopheline mosquito vectors, amid sustained poverty.
We remain unacceptably ignorant of the full extent of the public health burden posed
by this parasite; however, it is clear that, over time, the mortality effects of P. falciparum have been significant, serving as a potent selective force on the human genome to
confer red cell and hemoglobin genetic advantages against disease and death 3]. It is reasonable to assume that Africa has contributed most to the global malaria
burden for millennia.

Advances and challenges with malaria control

Incredible progress was made following the Second World War, with the discoveries
of DDT and chloroquine, shrinking the global extents of both P. vivax and P. falciparum, benefiting large parts of the Americas, Europe, and Asia. However, the elimination
ambition in sub-Saharan Africa came to an abrupt end by the early 1960s when it was
recognized that interrupting transmission with indoor residual house-spraying and/or
mass drug administration was almost impossible 4].

Revisiting this early literature has important implications for the control of malaria
today. First, targeting adult vectors and the parasite was far more successful than
targeting the vector alone 5]; second, despite not always being able to interrupt the incidence of new infections,
the disease burden and mortality plummeted to very low levels when there was complete
intervention coverage; finally when these ‘experiments’ came to an end, clinical and
fatal events returned quickly to pre-intervention levels and in some cases with worsened
consequences 6].

Malaria across Africa reached epidemic proportions in the 1990s 7], leading to the launch of a new global strategy in 2000 with Africa center stage.
During the Global Malaria Eradication campaign of the 1950s, building a national understanding
of the epidemiology of transmission, cartography of risk, endemicity, and vector species
distributions was vital. In addition, detailed pilot investigations molded decisions
on whether elimination was feasible, what was required, and where within a country
it might achieved. This level of epidemiological intelligence was absent at the launch
of the Roll Back Malaria campaign in 2000.

Epidemiological intelligence

The clinical epidemiology of P. falciparum is complex and interest in unraveling its mysteries goes back over 80 years. What
we do know is that repeated parasite exposure leads to the acquisition of a clinical
immunity that first protects against the severe consequences of infection, immunity
develops more slowly to the milder forms of the disease and much more slowly by regulating
the intensity of blood stage infection. We do not know how many new parasite exposures
are required to invoke a functional clinical immune response, but in areas where multiple
new infections are experienced quickly from birth, immunity is acquired faster than
in an area where the intensity of parasite transmission is much lower. This remains
one of the fundamental conceptual frameworks of malaria disease epidemiology that
governs the age and clinical patterns of health outcomes, rates of morbidity and mortality,
and the varying mixes of control options available on an elimination pathway (Figure 1).

Figure 1. Conceptual framework of the clinical epidemiology ofPlasmodium falciparumunder declining parasite transmission intensity in Africa.

There is evidence 8]-12] to suggest that despite a changing pathogenesis and age pattern of disease, the overall
rate of severe, life-threatening disease in childhood remains stable for a large part
of the transmission curve (bold line in Figure 1) and only when conditions within the mesoendemic range are reached do the rates of
disease begin to significantly decline. As transmission declines further, the risk
of infection becomes more directly related to the chances of becoming sick and developing
severe complications until a state is reached where infection risks and disease outcomes
are both rare. Lacking functional immunity, the consequences of any new infection
for an individual become increasingly severe. These unstable conditions become very
susceptible to even the smallest of perturbations in climate, ecology, population
movement, and intervention efficacy (drug and insecticide resistance) or coverage.

Throughout the transmission spectrum, malaria adheres to some basic infectious disease
principles: some people are more susceptible to a poor disease outcome than others,
some are bitten more frequently than others, and some are more infectious than others
13]. This heterogeneity becomes increasingly relevant to control with declining intensity
of transmission to the point below 1% PfPR _2–10, where foci of risks emerge. When elimination plans are activated, these sinks of
transmission become the target of intervention.

After a decade of Roll Back Malaria in Africa, almost 184 million Africans still live
under conditions of hyper-holoendemic transmission 12], despite impressive coverage of insecticide-treated nets (ITNs) since 2006. Mathematical
theory suggests that ITNs alone might not reduce parasite exposure enough in the highest
endemicity classes, even when deployed to protect over 80% of the population and used
every night 14],15]. The same theory suggests that ITNs with similar coverage and use will transition
communities from a natural mesoendemic range to the lower end of the hypoendemic range
within 5 to 8 years. There is an increasing body of evidence to suggest we are witnessing
intractable disease risks across the intense transmission belt of middle Africa; transmission
drops moderately, age patterns of disease re-align, but overall disease incidence
remains the same or rises 16]-20].

What is imperative is that sick patients are diagnosed properly and managed quickly
and with the right drugs. This is true across the entire transmission spectrum. The
vectors and the parasite are not going anywhere soon and there is a school of thought
that some of the greatest benefits will come when Africa is lifted out of poverty.
Urbanization will have an impact on vector abundance and species composition. Improved
health systems will increase access to therapeutics and prophylactics targeting the
parasite as well as the ability to track residual foci of risk. All would benefit
from a growing economy. It is no coincidence that malaria was finally eliminated from
southern European countries and the United States at times when economies were exponentially
expanding.