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- Materials and methods
Objective To explore the relationship between calendar month of administration and antibody (Ab) response to vaccination in subjects from The Gambia and Pakistan, two countries with distinct patterns of seasonality.
Methods Three cohorts were investigated: Responses to rabies and pneumococcal vaccine were assessed in 472 children (mean age 8 years, males 53%) from rural Gambia. Responses to tetanus, diphtheria and hepatitis B (HBsAg) were investigated in 138 infants also from The Gambia (birth to 52 weeks of age, males 54%). Responses to rabies and Vi typhoid vaccines were assessed in 257 adults from Lahore, Pakistan (mean age 29.4 years, males 57%).
Results In Gambian children, significant associations were observed between month of vaccination and Ab response for the pneumococcal and rabies vaccines. As no consistent pattern by month was observed between the responses, it is assumed that different immunomodulatory stimuli or mechanisms were involved. In Pakistani adults, a significant pattern by month of vaccination was observed with both rabies and typhoid vaccine. No monthly influences were observed in the infant study to the tetanus, diphtheria or the HbsAg vaccines.
Conclusions Antibody responses to certain specific vaccines are influenced by month of administration. Further research is required to elucidate the precise mechanisms explaining these observations, but a co-stimulatory effect of seasonally variable environmental antigens is a likely cause. Future studies of Ab response to vaccination in countries with a seasonally dependent environment should consider month of vaccination when interpreting study findings.
Objectif Etudier le lien entre le mois d'administration et la réponse anticorps à un vaccin chez des sujets vivants en Gambie et au Pakistan; deux pays ayant des modèles distincts de saisonnalité.
Méthodes Trois cohortes étaient étudiées: les réponses aux vaccins contre la rage et le pneumocoque étaient étudiées chez 472 enfants (âge moyen 8 ans, 53% de sexe masculin) en zone rurale en Gambie. Les réponses aux vaccins contre le tétanos, la diphtérie et l'hépatite B (Ag-HBs) étaient étudiées chez 138 nourrissons provenant également de Gambie (de la naissance à 52 semaines d’âge, 54% de sexe masculin). Les réponses aux vaccins contre la rage et la typhoïde (Vi) étaient étudiées chez 257 adultes à Lahore, Pakistan (âge moyen 29,4 ans, 57% de sexe masculin).
Résultats Chez les enfants Gambiens, des associations significatives étaient observées entre le mois de vaccination et la réponse anticorps pour les vaccins contre le pneumocoque et la rage. Comme aucune relation logique était observée entre le mois d'administration et les réponses vaccinales, il est possible que différents mécanismes ou stimuli immuno-modulateurs soient impliqués. Chez les adultes Pakistanais, un lien significatif avec le mois de vaccination était observé avec les 2 vaccins contre la rage et la typhoïde. Aucune influence du mois était observé dans l’étude de la vaccination contre le tétanos, la diphtérie et l'hépatite B chez les nourrissons.
Conclusions La réponse anticorps à certains vaccins spécifiques est influencée par le mois d'administration. D'autres études sont nécessaires pour élucider le mécanismes précis pouvant expliquer ces observations, mais un effet co-stimulateur d'antigènes environnementaux variants selon les saisons est probablement en cause.
Objetivo Explorar la relación entre el calendario mensual de administración de vacunas y la respuesta de anticuerpos en sujetos de Gambia y Pakistán; dos países con diferentes patrones de estacionalidad.
Métodos Se investigaron tres cohortes: se evaluaron las respuestas a la vacuna de la rabia y a la vacuna neumocócica en 472 niños (edad promedio 8 años, varones 53%) de áreas rurales de Gambia. Se investigaron las respuestas al tétanos, difteria y hepatitis B (HBsAg) en 138 infantes también de Gambia (desde el nacimiento a las 52 semanas de edad, varones el 54%). Se establecieron las respuestas a las vacunas de la rabia y de la Vi tifoidea en 257 adultos de Lahore, Pakistán (promedio de edad 29.4 años, y varones un 57%).
Resultados En los niños de Gambia, se observaron significantes asociaciones entre el mes de vacunación y la respuesta de anticuerpos para las vacunas neumocócicas y de la rabia. Dado que no se observó un consistente patrón por mes entre las respuestas, se asume que diferentes mecanismos o estímulos inmunomoduladores han estado involucrados. En adultos paquistaníes, un significativo patrón en el mes de vacunación fue observado tanto en la vacuna tifoidea como en la de la rabia. No se observaron influencias en el mes en el estudio de los infantes en las vacunas del tétanos, difteria o HbsAg.
Conclusiones Las respuestas de anticuerpos a ciertas vacunas específicas están influenciadas por el mes de administración. Es necesario más investigación para dilucidar los mecanismos precisos que expliquen estas observaciones, pero un efecto coestimulador de antígenos de variables ambientales estacionales es una causa probable. Los futuros estudios de respuesta de anticuerpos a las vacunas en países con un medio ambiente dependiente de las estaciones deberán considerar el mes de vacunación al momento de interpretar los hallazgos del estudio.
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- Materials and methods
Vaccination, together with sanitation, has made the most important contribution to public health in the past century, and has dramatically reduced the number of deaths attributed to infectious disease across the world. Many such vaccines are now easily available to all, and programmes such as the expanded programme of immunization (EPI) reach people even in the world's poorest countries. While most commercially produced vaccines elicit a protective response in most recipients, evidence suggests that a number of factors can influence the strength of the response between individuals. Considering these factors in studies of antibody (Ab) response to vaccination is therefore important.
Age at vaccination is the most commonly recognized to influence Ab responses, with variations specifically seen in the young and the elderly. In early life, numerous factors contribute to the limitation of Ab responses to both protein and polysaccharide vaccines. One factor is immunological immaturity, which may affect B cells and/or their interactions with antigen-presenting cells, T cells, follicular dendritic cells or other components of the lymphoid microenvironment (Siegrist 2001). Pre-existing maternal Ab levels are another factor: they may limit vaccine response through various mechanisms (Siegrist 2003), or stimulate vaccine response through breastfeeding, including specific enhancement of the immunoglobulin G2 response during Haemophilus influenzae type b (Hib) disease in childhood (Silfverdal et al. 2002). In the elderly, age-related changes in various aspects of immune function, such as an increase in the number of immune cells showing signs of replicative senescence, result in a reduced Ab response to vaccination (Rubins et al. 1998; Fisman et al. 2002) and underscore the need for specific research aimed at designing vaccines to meet the unique requirements of this population.
Gender is also thought to influence Ab response to vaccination, and it is suggested that the immune system is clearly dimorphic, with female animals from different species having higher levels of circulating immunoglobulins and presenting stronger Ab responses to immunization and infection (Da-Silva 1999). Hypothesized mechanisms for such differences include the differential modulation of immune factors by sex hormones (Da-Silva 1999).
Other suggested modifying factors include nutritional status and certain infections. In many countries, the distinct seasons define patterns in disease prevalence and nutritional status. Thus, season of administration may influence the Ab levels generated. We explored the effect that the month of vaccination had on Ab generation in three age groups of subjects from two countries exhibiting a distinct seasonal pattern: an infant cohort from The Gambia, West Africa; a child cohort also from The Gambia and an adult cohort from Lahore, Pakistan.
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- Materials and methods
A number of factors are thought to influence an individual's response to certain commonly used vaccines. Such factors include age, gender, nutritional status and infection at the time of vaccination. The current study has added to this evidence, with data to suggest that month of administration in two countries with a pronounced seasonality influences the serum Ab levels generated in different population groups and using a number of different vaccines.
A seasonal variation in markers of immune function has been reported in studies from West Africa. In The Gambia, we observed a seasonal variation in blood leucocyte and lymphocyte subpopulations measured during infancy, with higher lymphocyte and leucocyte counts in the rainy season (July–December), when compared with the dry season (January–June) (Collinson 2002). In a study of infants and children from Guinea-Bissau, however, Lisse et al. (1997) actually reported the opposite with lower absolute and percentage lymphocyte counts observed in samples collected during the annual rainy season. In addition, from Guinea-Bissau, Shaheen et al. (1996) found a seasonal variation in cell-mediated immunity, with a rise in anergy (a negative skin test response observed to all test antigens) observed during the rainy season. In The Gambia, we also saw a variation by season of measurement in the size of the thymus, as assessed by ultrasonography. At each age point (1, 8, 16 and 52 weeks of age) the mean thymic index was significantly smaller in infants when measured in the wet season (Collinson et al. 2003). This observation correlated with a seasonal variation in breast milk IL-7 levels, suggesting a possible role of breast milk immune factors in promoting thymic development (N'Gom et al. 2004). However, the studies reported in this paper are the first example we can find in the literature to report that month of administration of some commercially produced vaccines influences Ab response.
There are a variety of seasonally related factors that could account for this observed difference in Ab response. First, it is possible that it could be a consequence of methodological problems directly related to month of vaccination, such as differences in ambient temperature affecting the cold chain of the vaccines. However, this is considered highly unlikely in the current studies, as the vaccines were stored and administered under research protocol standards. In addition, batch differences in the vaccines cannot account for these observations, as in both the child cohort in The Gambia and the adult cohort in Pakistan where seasonal associations were observed, the same batch of vaccines was used for all subjects.
It is possible that the observed association is a consequence of the seasonal pattern in infectious or background antigen exposure in both these population groups. In rural Gambia, there is a profound seasonality in malaria transmission, with highest rates of hospital admissions observed in the rainy season months of October and November (Brewster & Greenwood 1993). Seasonal differences in either parasitaemia or malaria prophylaxis/treatment could therefore influence the Ab response to vaccination. Indeed, previous studies have shown an association between acute malaria and a decreased response to certain vaccines, including diphtheria and tetanus toxoid, and to meningococcal, Salmonella and Hib vaccinations (reviewed in Rosen & Breman 2004). While this could be a proposed mechanism for the associations observed, it seems unlikely, as children in The Gambia having blood films positive for parasites did not show a decreased response to either of the vaccines administered. In addition, plasma levels of ACT, indicative of an acute inflammation, did not account for the seasonal variation in Ab responses. Furthermore, and while a limitation of the current analysis is the truncated nature of data collection in the Pakistan study, with data collected between the months of April and September only, the relevance of a month by month variation in Ab response in a population where there is little malaria (Zaman et al. 1993), makes it unlikely that malaria infection is the primary causal factor in the observed association with month of vaccination. Of interest, and as malaria is known to affect the maternal Ab transfer (Duffy 2003), it may appear surprising that no association was observed between month of vaccination and pre-immunization levels to tetanus toxoid. However, malaria prophylaxis is prescribed routinely to pregnant women during the malaria season in this region of The Gambia, and very few placentas had evidence of active infection at the time of delivery and only a minority had evidence of malaria infection in earlier pregnancy (Collinson 2002). The large variance in cord and pre-immunization tetanus Ab levels coupled with small sizes of malaria-infected and -uninfected subgroups would, therefore give a low likelihood of detecting a seasonal effect of gestational malaria in this population cohort.
The associations with month of vaccination could also be due to other seasonally dependent infectious agents or environmental antigens. Studies from The Gambia have reported seasonal variations in the incidence of clinical presentation with both respiratory infections (Forgie et al. 1991; Brewster & Greenwood 1993) and diarrhoeal disease (Rowland et al. 1985; Brewster & Greenwood 1993), both showing peaks during and shortly after the annual rainy season. In Pakistan, a seasonal variation has also been reported in both upper and lower respiratory tract infections, with the reported incidence being highest during the cooler months of November to February (Zaman et al. 1993). In addition, a seasonal variation has been observed in the presence of diarrhoeal disease, with the maximum incidence observed during the months of April to June (Mahmud et al. 1993). While less is known about the seasonality of specific helminthic infections at either of the study sites, it is also possible that the current observations are the consequence of immune priming by infestations with worms.
Of specific relevance to the current study, a seasonal pattern in pneumococcal carriage has been observed in both infants and their mothers in The Gambia (Momodou Darboe, personal communication), with an apparent reduction in carriage during the months of May to August. Although the data are not directly comparable (collected in different years and from different subjects), this reduction in rates of carriage does seem to coincide with a reduced Ab response to the pneumococcal vaccine, and hence may suggest a priming of vaccine response by carriage. Priming by vaccine-specific Ab carriage cannot, however, explain the observed seasonal response for vaccines where no pre-vaccination carriage occurs (e.g. rabies). Further modelling of specific disease patterns in relation to Ab response may help elucidate whether the observed associations have an infectious aetiology.
There is some evidence in the literature to suggest that nutritional status may influence immune function, although such findings are not universal. It is also possible, therefore, that the observed difference is due to seasonal changes in the nutritional status of individuals living in these two areas. In rural Gambia, there is a pronounced seasonality in many markers of nutritional status: in energy balance (Prentice et al. 1981) and the status of certain micronutrients including vitamin A and its precursors (Bates et al. 1994), riboflavin (Bates et al. 1994), vitamin C (Bates et al. 1982,1994), iron (Bates & Prentice 1999) and folate (Bates et al. 1994). Although there are few published data describing the seasonality of nutritional status in urban Pakistan, it is unlikely that the variability of seasonally available foods will influence nutritional status in the population, and particularly in the urban poor. Studies looking specifically at vaccine response indicate that, while Ab production may be impaired in severe malnutrition (Powell 1982), in subjects with less severe nutritional deficiencies, there is no impact of nutritional status on Ab response to vaccination (Greenwood et al. 1986; Lakshami et al. 2000). Indeed, we have published elsewhere a detailed study to show that the Ab response to vaccination in rural Gambia is not related to nutritional status (Moore et al. 2003). It is therefore unlikely that the seasonal swings observed in nutritional status are responsible for the observed differences in Ab production to vaccination.
It is interesting that there were no associations between month of administration of the vaccine and Ab levels in the infant cohort from The Gambia. One possible reason is that the sample size in each group was too small, and that a larger population sample would be required to observe an association. Optionally, it may be that the strength of the Ab response to the specific vaccines used in the infant study (standard EPI vaccines) is not affected by the factors influencing the trends observed by month of vaccination in the other two studies. It is also possible, however, that an association with season includes the dimension of age, and that in infants, whose immune system is still relatively naïve, the level of the antigen exposure induced on vaccination is potent enough to induce a strong response in all, irrespective of other seasonally dependent factors. Alternatively, the diphtheria and tetanus Ab levels were measured in children at 16 weeks; an age at which most infants in this community are still predominantly breast fed and quite well protected from the morbidity and antigenic exposure associated with poor weaning practices. However, the fact that no association was observed with Hepatitis B Ab levels at 52 weeks of age suggests that the protective effect of breast milk is not the only factor influencing the lack of an association with month in this cohort. Finally, failure to detect a true effect in this age group might be a consequence of our choice of sample time points in relation to vaccine doses.
Understanding these associations could be aided by understanding the specific mechanisms of Ab generation to vaccination, as it is possible that the observed difference in response is a consequence of a selective response by certain types of vaccines. We used vaccines that can be immunologically classified as T-lymphocyte dependent (rabies, tetanus, diphtheria, Hepatitis B) or T-lymphocyte independent (typhoid and pneumoccocal). Indeed, from study 1 in The Gambia, the patterns of Ab response to the rabies and pneumococcal vaccines do not correlate, and it may be that different priming mechanisms are involved. Furthermore, we did not observe a single common pattern for the four different pneumococcal serotypes measured, possibly suggesting that differing patterns of exposure and carriage within this Gambian environment can drive later Ab-specific responses. Comparison of the effects of month of administration of vaccines from other studies in such seasonally affected population groups may help explain this observation.
It is also possible that we are observing an ‘adjuvant’ effect on Ab response. Adjuvants, such as aluminium hydroxide (alum) and calcium phosphate, are intentionally used in vaccines to elicit an early, high and long-lasting immune response. It is plausible therefore that other seasonally dependent non-infectious environmental antigens are having an adjuvant effect on the vaccine, and hence boosting the Ab response at specific times of the year. The apparent rise in Ab response to the second dose of the rabies vaccine during the months of July and August in Lahore supports the hypothesis of an adjuvant effect; an environmental exposure occurring most strongly in these two months might be driving the pronounced effects on Ab responses at this time. Elucidating and understanding the cause and mechanisms for this could be helpful in vaccine development and usage in such population groups.
In the current analysis, we have demonstrated a significant variation in Ab response to vaccination according to month of vaccination in studies from rural Gambia and urban Pakistan. Despite consideration of the many seasonally varying environmental factors, the aetiology for this observation is still not clear. We have not yet followed up any of the subjects included in the current analysis to explore whether the observed variance in Ab levels shortly after vaccination is maintained in the future, but this would be of interest. It would also be useful to understand which other vaccines are related to month of administration, and whether this is just a phenomenon unique to countries where the pattern in seasonality is known to influence many factors in life. Indeed, the specific impact of a seasonally defined reduced response to vaccination would need to be considered on a case-by-case basis. If seasonally related deficits were detected, it might be appropriate to consider selective additional booster vaccine doses for children immunized in a month/season during which responses have been predicted to be low. However, and as the majority of vaccines used in vaccination programmes such as the EPI elicit an appropriate response from the majority of recipients, this finding may be most relevant in the interpretation of vaccine trial data from such population settings and in understanding in more detail mechanisms for potential seasonal interactions at an immunological level.