Copyright © 2014 Elsevier Ltd All rights reserved.
Ebola control: effect of asymptomatic infection and acquired immunity
Evidence suggests that many Ebola infections are asymptomatic,1, 2 a factor overlooked by recent outbreak summaries and projections.3 Particularly, results from one post-Ebola outbreak serosurvey1 showed that 71% of seropositive individuals did not have the disease; another study2
reported that 46% of asymptomatic close contacts of patients with Ebola
were seropositive. Although asymptomatic infections are unlikely to be
infectious,2 they might confer protective immunity and thus have important epidemiological consequences.
Although
a forceful response is needed, forecasts that ignore naturally acquired
immunity from asymptomatic infections overestimate incidence late in
epidemics. We illustrate this point by comparing the projections of two
simple models based on the Ebola epidemic in Liberia, a model that does
not account for asymptomatic infections, and another that assumes 50% of
infections are asymptomatic and induce protective immunity. In both
models, the basic reproduction number (R0) is identical and based on published estimates.3 The figure
shows the projected cumulative incidence through time. Although the
initial outbreaks are almost identical, by Jan 10, the model without
asymptomatic infections projects 50% more cumulative symptomatic cases
than the model that accounts for asymptomatic infection. This difference
arises because asymptomatic infection contributes to herd immunity and
thereby dampens epidemic spread.
Widespread
asymptomatic immunity would likewise have implications for Ebola
control measures and should be considered when planning intervention
strategies. For instance, should a safe and effective vaccine become
available, the vaccination coverage needed for elimination will depend
on pre-existing immunity in the population (appendix).
Immunity resulting from asymptomatic infections should reduce the
intervention effort needed to interrupt transmission but might also
complicate the design and interpretation of vaccine trials. Trials and
interventions are likely to target exactly those high-risk populations
most likely to have been asymptomatically immunised. Thus, for
assessment of vaccines and other countermeasures, baseline serum should
be collected to improve both estimates of intervention effectiveness and
our understanding of asymptomatic immunity. Additionally, assessment of
intervention measures should account for the contribution of
asymptomatic immunity in curbing epidemic spread.
Asymptomatic
infection could also potentially be directly harnessed to mitigate
transmission. If individuals who have cleared asymptomatic infections
could be identified reliably, and if they are indeed immune to
symptomatic re-infection, they could potentially be recruited to serve
as caregivers or to undertake other high-risk disease control tasks,
providing a buffer akin to that of ring vaccination. Recruitment of such
individuals might be preferable to enlistment of survivors of
symptomatic Ebola disease because survivors might experience
psychological trauma or stigmatisation and be fewer in number—in view of
the asymptomatic proportions suggested in previous studies1, 2 and the low survival rate of symptomatic cases.3
Health-care workers with natural immunity acquired from asymptomatic
infection, if identified, could be allocated to care for acutely ill and
infectious patients, minimising disease spread to susceptible
health-care workers.
The conclusions
above depend on whether asymptomatic infections are common, and
protective against future infection. Further, strategies to leverage
protective immunity will depend on the development and validation of
assays that can reliably identify individuals who are effectively
protected against re-infection. Previous studies have identified many
asymptomatic infections using IgM and IgG antibody assays and PCR,1, 2 which, although indicative of infection, do not necessarily imply protective immunity.4 Evidence for long-term protective immunity reported in (symptomatic) Ebola survivors is suggestive,4
but the extent of protective immunity after asymptomatic infection and
the identification of serological markers for protective immunity can
only be definitively addressed in settings with ongoing transmission
risk. As has been proposed for vaccination,5
the epidemic therefore provides a unique opportunity to investigate
asymptomatically acquired protective immunity to Ebola virus. Although
resources are scarce, now is the time for interventions protecting
people at risk of contracting Ebola (ie, health-care workers and
household caregivers) to incorporate serological assessments to
ascertain asymptomatic infections—feasible with even introduced cases
such as recently occurred in Dallas, Texas—and immunological correlates
of protection—feasible only in settings with ongoing transmission.
A
more direct investigation of asymptomatically acquired immunity might
be possible by leveraging proposed trials to assess the efficacy of
blood transfusions from Ebola survivors.6
During the 1995 outbreak in DR Congo, a study reported increased
survival rates in transfusion recipients but was potentially confounded
by the superior supportive care afforded to the treated patients.7 Burnouf and colleagues6
have advocated for randomised controlled clinical trials comparing the
treatment efficacy of transfusions from survivors with those from
control donors. By including a third study group in which patients
receive transfusions from asymptomatic seropositive individuals, this
design could simultaneously assess the therapeutic value of these
transfusions from asymptomatic individuals, and indicate whether such
individuals have protective immunity.
We
propose that launching of an immediate investigation of asymptomatic
immunity, by coupling serological testing to ongoing intervention
efforts in west Africa, is warranted and feasible, and might ultimately
save lives.
We thank David Champredon,
Stephanie Cinkovich, and Spencer Fox for assistance with reviewing the
literature, and Carl Pearson for helpful discussions. We acknowledge
support from NIGMS, MIDAS, RAPIDD, NIH, CIHR, and NSERC.
We declare no competing interests.
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