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explain satisfactorily the conundrum of the high rate of vivax malaria (pre-
sumably relapses), which follows falciparum malaria in endemic areas of
East Asia. It follows from this that the number of early relapses per mos-
quito inoculation will decrease with increasing age in endemic areas as the
stimulus to hypnozoite activation declines with increasing disease control-
ling immunity, and immunity increases the probability that the relapse is
asymptomatic. In Thailand, the incidence of symptomatic P. vivax malaria
peaks in childhood, but P. vivax following P. falciparum malaria shows a
weaker age relationship. Thus, P. falciparum may contribute significantly to
P. vivax transmission, particularly in young adults, through this mechanism.
This emphasises the importance of considering the two species together
and not in isolation. With small-sporozoite inocula, it is quite possible for
all sporozoites to develop immediately (early infection, no relapses) or for
all to result in hypnozoites, and all the hypnozoites to become latent (no
early infection as no activation stimulus, the first infection follows a later
activation stimulus such as a malaria illness).
For temperate strains of P. vivax , there are clearly at least two popu-
lations of hypnozoites, one becoming activatable early (as for tropical
P. vivax ) and another remaining latent and not immediately activatable. To
study activation during the latent period, Cooper et al. gave homologous
(St. Elizabeth strain) infections by blood 120 days after subjects had been
infected with the same strain by mosquito bites ( Cooper et al., 1947 ). The
blood inoculations reliably gave symptomatic malaria but critically, they
did not affect the timing of the subsequent relapse. This shows that the
hypnozoites half way through their sleep were absolutely refractory. This
supports the concept of a biological clock for the long-latency P. vivax . In
order to account for the distribution of long latencies, it is likely that once
hypnozoites do become activatable, that there is a background relatively
low rate of spontaneous activation. Thus, for the long-latency P. vivax , the
first relapse after the long-latent period is usually spontaneous (i.e. there
is no external activation stimulus), but the illness then activates further
hypnozoites, accounting for the subsequent short inter-relapse intervals. If
this is correct, it follows that first relapses, which occur with a long-latency
interval (i.e. 8-10 months after the primary infection), should usually be of
a similar genotype to the initial infection, whereas relapses at other times
could be heterologous. This has been observed recently in Kolkata ( Kim
et al., 2012 ) ( Fig. 2.7 ). If there are subsequent relapses, i.e. which follow the
first relapse after the latent period (i.e. with a short periodicity), then these
could be genetically heterologous.
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