Possible changes in the transmissibility of trachoma following MDA and transmission reduction: implications for the GET2020 goals

In this study we hypothesise that successive MDA treatment rounds and rapid transmission
reduction measures may lead to an increase in transmissibility of trachoma infection,
and an increase in difficulty in controlling disease. This could be due to the gradual
loss of immunity from the population following treatment. This effect was most pronounced
for the lowest prevalence communities, in which transmission was low and control may
be achievable despite it. However, in these communities, while control is feasible,
elimination may become markedly more difficult over time if R _e
doubles over 20 years (as in Fig. 4). In hyperendemic communities, reductions in immunity result in a smaller transmissibility
rise but, in the context of the extremely labour-intensive treatment schedules needed
to achieve year-on-year declines in prevalence 14], 31], 32], even a marginal additional effort will be hard to maintain.

The increasingly rapid return of infection over time can be explained by the following
process: first, sustained treatment prevents the population from progressing towards
greater numbers of infections, which means that the population experiences fewer infections,
on average; second, due to the slower rate of acquiring clearing immunity due to treatment
and transmission reduction, individuals remain infected for longer periods of time,
increasing the force of infection.

While our results in this study are theoretical, the rationale behind them has a sound
biological basis. Recent work by Mitchell et al. 5] found that if protective immunity to schistosomiasis was short-lived, antibody levels
declined to pre-intervention levels during or after MDA. However, if immunity was
longer-lived and MDA was assumed to reduce transmission, a large over-shoot in measured
egg count was observed. This modelling work was supported by antibody data suggesting
MDA and transmission reduction may disrupt the development of protective immunity
or alter existing population immunity 5].

The hypothesis presented in this article has been quantitatively tested just once
for trachoma, to our knowledge, within a mesoendemic community, by Liu et al. 19]. While the authors did not identify a significant change in R _e
over the 3 year period analysed, the analysis presented here suggests that a strong
signal of increase in R _e
may only become apparent after several years, and that its initial increase may be
small.

Our simulated MDA assumes random allocation of doses in the population with each treatment,
while a persistently untreated group of individuals is also a possibility. In the
latter case, it is likely that the value of R _e
would increase more slowly and to a lesser overall extent due to a more rapid reseeding
of infection from the untreated group into the wider population following each treatment
round.

The adverse effect we find applies to communities in which MDA is introduced in isolation,
but it may be exacerbated when dramatic transmission reduction measures are rapidly
implemented. Such an outcome has previously been suggested for malaria 10], 12]. In this instance it is expected that a higher number of severe disease cases will
be observed immediately following the reduction in transmission, primarily as a result
of the loss of population immunity. Furthermore, epidemiological surveillance data
in genital chlamydia infection has also shown empirical evidence of this effect 22], 23]. It was reported that re-infection rates following the introduction of an infection
control programme resulted in a 4.6 % per year re-infection rate increase during the
period of study from 1989–2003 22]. These findings were complemented with a mathematical transmission model suggesting
that early treatment of infection increased the population’s susceptibility to re-infection
22]. However, Vickers et al. 33] suggested that the increased rates of re-infection in Canada could mainly be attributable
to an increase in testing volume, implying that The Arrested Immunity Hypothesis had a less significant role on the transmission dynamics than previously reported
36].

To date, the analysis of serological data collected through trachoma surveillance
has been very limited 34], 35]. Martin et al. 35] fitted a catalytic model to serological data in order to identify when changes in
transmission intensity within a Tanzanian community occurred. The authors used a binary
cut-off to determine whether individuals in the study were seropositive or seronegative
and, during the surveillance period, they did not identify any individuals who seroreverted,
suggesting no loss of population immunity. However, the use of a binary cut-off to
define individuals as seropositive or seronegative can mask changes in the antibody
titres that may occur over time, meaning that even if an individual’s titre has declined
dramatically, if it does not fall below the cut-off threshold, they will still be
classified as seropositive. Indeed, Goodhew et al. 34] showed that there was evidence of a significant decline in trachoma antigens for
nearly all age groups 6 months after MDA was applied. Anti-trachoma antibodies are
likely to be associated with protection although the exact relationship is poorly
understood. Antibody titers may decrease over time while an individual remains seropositive
leading to a likely decrease in protection over time.

Therefore, while the effects presented here remain to be substantiated with data from
treatment and transmission reduction trachoma trials, we suggest the effect seen for
genital chlamydia and schistosomiasis should be motivation to design trials which
include these outcomes.