Circulating strains of wild pathogen vary over time and location. A standard vaccine formulation is not necessarily equally effective for all circulating strains. So, for example, when commenting on different efficacy results for Hib vaccine trials in Cuba and Brazil, one of the factors postulated was a variation in the bacteria.
Brazil is a continent of a country, and we have polymorphisms of bacteria . . . There are some bacteria which we are unable to type. . . We are talking about cross-reactivity, but we have no good evidence to support the idea that we can protect based on cross-reactivity against the challenge given by a very broad range of polymorphic bacteria. (Prigenzi in Broome 1991, p 223)
This has also been discussed as a factor contributing to variations in the results obtained when evaluating pertussis vaccines.
There is the question of whether the efficacy of some vaccines might be different for different strains of B. pertussis . . . we may presume that bacterial populations which differ in serotype will differ in various other ecological or biochemical characteristics – some of which might be relevant for vaccines. (Fine 1997, p 130)
This is another factor to consider, as epidemiological studies rarely report on the strains or subtypes of the target pathogen circulating in the local population at the time of a study, though this may have an impact on the observed results.
8.6 BROADER IMPLICATIONS OF VACCINE EFFICACY TRIALS
Vaccine efficacy trials usually have a very specific aim: to prove that a particular vaccine reduces the incidence of a particular disease in a target population, and sometimes to support this with evidence of increased levels of pathogen specific serum antibody in individuals who received the vaccine. This is understandable, as the primary aim is to provide proof of performance sufficient to satisfy licensing regulations. However, the result is that consideration is rarely given to any broader conditions surrounding administration of the vaccine, nor are potential non-specific effects of vaccine administration examined, unless they relate to claims of
suspected adverse effects.
That vaccines may have non-specific, long-term effects on the general health of a population was highlighted by recent unexpected findings with the measles
vaccine.
Evaluations of immunisation programmes are usually based on the assumption that vaccines have an impact only against specific diseases. This assumption may not be correct for measles vaccine. (Aaby et al 1995, p 481)
It was found that recipients of a new high-titre measles vaccine, and particularly girls, had a reduced level of long-term survival compared with recipients of standard-titre vaccines. Recipients of standard-titre vaccines had an increased level of long-term survival, compared with unvaccinated children, in areas with high mortality. These effects were non-specific, that is, the variations in mortality levels were not associated with exposure to measles virus.
The explanation offered is that the measles vaccine provides a non-specific stimulus to the immune system which assists in providing protection from other infections (Aaby et al 1995). This is also an assertion that has been made about survival from natural measles infection (AVN 1998; Scheibner 1993). This proposition is compatible with the evidence presented above that the basis of immunity provided by a particular vaccine is broader and more complex than simply the production of pathogen specific serum antibodies.
There are other pathogen related issues that need more detailed consideration in the design and reporting of vaccine efficacy trials. These include:
The background incidence of the disease.
Currently circulating strains of the wild pathogen.
The general epidemiology of the disease.
Intensity of exposure (eg cases of disease in the household and local community)
The proportion of the population that have already received a previously licensed version of the vaccine.
That previous exposure to apparently unrelated pathogens may have an influence on response to the current vaccine.
The background incidence of the disease is an important consideration in
a new vaccine may be very different in a situation where there is a current
outbreak, compared with a situation where the background incidence is very low. In a retrospective examination of several studies on 12 different pertussis vaccines accurate comparison of results was difficult because a number of parameters were not adequately reported. Background incidence of pertussis disease was one of them:
The fact that pertussis appears in epidemic cycles makes it difficult to compare exposures in general population settings . . . (Fine 1997, p 130)
Related to this issue is the intensity and source of exposure to the pathogen.
The influence of intensity of exposure on the performance of pertussis vaccines is unclear. One might expect that exposure intensity is much higher under conditions of household exposure than in a general population setting. (Fine 1997, p 130)
Aaby & Molbak (1992) found that more severe cases of measles in children were likely to occur if the contact was of the opposite sex, and that this overrode the effect of household exposure.
Currently circulating strains of the relevant pathogen is another important
parameter that requires more thorough reporting. Studies rarely provide details of the particular strains of wild virus that are prevalent in the study population, although this could be important information in determining whether a vaccine is effective against some strains but not others (Fine 1997).
Related to this is the need to report on any other prevalent pathogens, as broader or cross-pathogenic effects may be discovered.
It is likely that the Senegal children differed from the Europeans in terms of maternal antibody profiles and various intercurrent infections, which might
have influenced their responses to pertussis vaccine antigens. (Fine 1997, p 130)
This is particularly important in areas where there is a high incidence of serious conditions such as Hepatitis B or malaria (NHMRC 2000a).
The general epidemiology of the target pathogen in the study population has also been shown to influence efficacy data. For example when a conjugate Hib vaccine was shown to have a protective efficacy of 87-90% in Finish infants, but only 34% in Alaskan infants it was thought that:
Probably the most important reason for the low protective efficacy in the Alaskan study was the different epidemiology of the disease: it has a higher incidence and occurs at an earlier age in Alaska than in Finland. (Käyhty 1994, p 399)
It is also well documented that pertussis has a higher incidence where adults act as a reservoir (Cherry 1996).