Partially effective vaccines that fail to block infection are likely to be worse than useless, according to a new theoretical model. This study should provide substance for informed debate over a wide range of vaccines, including those against biowarfare attacks. Dr. Mae-Wan Ho reports.
Vaccines rarely provide full protection from disease. What are the likely consequences of partially effective vaccines? It depends on the way the vaccine works, according to a new theoretical study published in Nature at the end of last year by researchers in the Institute of Cell, Animal and Population Biology, University of Edinburgh .
Vaccines designed to reduce pathogen growth rate and/or toxicity tend to lead to evolve to higher levels of virulence (ability to infect and cause disease) of the pathogen and hence to more severe disease in unvaccinated individuals. This can erode any population-wide benefits. For example, overall mortality rates may remain unchanged, or even increase, with the level of vaccination coverage. In contrast, infection-blocking vaccines induce no such effects, and can lead to lower virulence. "These findings have policy implications for the development and use of vaccines that are not expected to provide full immunity, such as candidate vaccines for malaria".
The same applies to a whole range of other vaccines that are being developed against AIDS (see "Doubts deepen over AIDS vaccines") and other diseases, including those against biowarfare agents.
The model distinguishes four different forms of immunity aimed at different stages of the pathogens life cycle. The first works against infection, which decreases the probability that a host becomes infected. The second reduces growth rate, which directly reduces virulence and also affects transmission rate and host recovery. The third blocks transmission directly. The fourth reduces severity of disease by neutralising the toxic effects, which directly reduces virulence, but does not affect parasite transmission and rates of host recovery.
The host-parasite (human-pathogen) populations are allowed to evolve with feedback until they reach a stable point (equilibrium), the pathogen mutating while the host population remains genetically unchanged and uniform. The model predicts, counter to expectation, that anti-growth rate and anti-toxin immunity, by reducing the death of infected hosts, always leads to higher virulence. In contrast, anti-infection and transmission-blocking lead to lower virulence or leave virulence unchanged.
In a heterogeneous population of susceptible and resistant hosts, as would be the case if a vaccination programme were implemented, parasite virulence increases sharply without limit when the vaccine is directed against the toxic effects. In a strategy that reduces the growth rate of the pathogen, virulence also increases sharply until growth-rate reduction is very effective, at which point, virulence drops precipitously.
In contrast, strategies that reduces infection or transmission both lead to reduction in virulence.
This new analysis assumes that hosts and pathogens reach dynamic equilibrium. Many diseases, however, have more complex dynamics, which may exhibit cycles or chaotic behaviour. However, the effects of imperfect vaccines are not qualitatively altered by those complications, according to the authors.
Current efforts to develop a malaria vaccine are focussing on three different stages of the parasites life cycle - the pre-erythrocyte stages (before blood cells, sporozoites and liver-stage parasites), asexual blood-stage (merozoites and infected erythrocytes) and the mosquito-stage (gametocytes, gametes, ookinetes), corresponding to the anti-infection, anti-growth-rate and transmission-blocking forms of resistance. Anti-toxin malaria vaccines are also being explored.
Using a modified form of the general model to incorporate two important features of malaria epidemiology - naturally acquired immunity and vector transmission - the authors investigated the public health consequences of using various vaccines.
The same results were obtained as in the general model, except that transmission-blocking vaccines may favour slightly higher virulence. Combining all four different strategies lead to higher pathogen virulence despite the beneficial effect of anti-infection vaccines.
Anti-infection and transmission-blocking vaccines reduce the force of infection and hence malaria prevalence. In contrast, anti-growth and anti-toxin vaccines have hardly any effect on prevalence. Combining anti-infection and anti-transmission effects is the most efficient in reducing malaria prevalence, and could even lead to eradication of the disease.
A crucial feature of all the models is that the pathogen is assumed to evolve, as it does in real life.
The efficacy of anti-infection measures strongly supports the use of other partially effective control methods, the authors recommend, for example, bednets and mosquito control, to enhance the long-term benefits of vaccination (see "Two takes on malaria", Science in Society 13/14, February 2002 ).
Article first published 30/04/02
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