Article

Low mortality after mild measles infection compared to uninfected children in rural West Africa

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Abstract

It has been assumed that measles infection may be associated with persistent immune suppression and long-term excess mortality. However, few community studies of mortality after measles infection have been carried out. We examined long-term mortality for measles cases, sub-clinical measles cases, and uninfected contacts after an epidemic in rural Senegal. The study was carried out in Niakhar, a rural area of Senegal. Index cases of measles were identified and children less than 7 years of age exposed to measles in the same compound had acute and convalescent blood samples collected. Clinically diagnosed measles cases were serologically confirmed. Children without clinical symptoms were classified as sub-clinical cases if they had a four-fold or greater change in antibody levels between samples collected at exposure and 1 month later and as uninfected if there was no or a two-fold change in antibody levels. There were 31 index cases, and among 184 exposed contacts, 35 (19%) children developed clinical measles. Among contacts that did not develop clinical measles, 45% had sub-clinical infection. Measles cases, sub-clinical cases, and uninfected contacts did not differ with respect to nutritional status. However, uninfected children without clinical symptoms and change in antibody level had higher initial measles specific IgG antibody levels and less intensive exposure to the index case. No index or secondary case of measles died in the acute phase of infection nor did any of the children exposed to measles die in the first 2 months after exposure. Exposed children developing clinical measles had lower age-adjusted mortality over the next 4 years than exposed children who did not develop clinical measles (P<0.05). Sub-clinical measles cases tended to have low mortality and compared with uninfected children, exposed children with clinical or sub-clinical measles had lower age-adjusted mortality (mortality ratio (MR)=0.20 (0.06-0.74)). Controlling for background factors had no impact of the estimates. When measles infection is mild, clinical measles has no long-term excess mortality and may be associated with better overall survival than no clinical measles infection. Sub-clinical measles is common among immunised children and is not associated with excess mortality.

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... Details of the demographic data collection have already been provided by Delaunay [19]. Préziosi et al. [20] and Aaby et al. [21] have detailed the survey's methodology for whooping cough and measles, respectively. Campaigns of mass vaccination against both infections started at the end of 1986. ...
... In spite of this, pertussis remains endemic with epidemic outbreaks every 3–4 years. Measles vaccine coverage has also been irregular in time; it increased among 1-to 2-year-old children from 36% in 1987 to 81% in 1992 [21], but declined again in 1997. Accounting for these changes, vaccine coverage in the whole population was around 38%. Measles also remains endemic in Niakhar. ...
... This study showed the impact of vaccination at three spatial scales. At the individual level, immunisation significantly increased the mean ages at infection, as already described in the zone for a shorter period [20,21], and a drop in their basic reproductive rate. Interestingly, its impact on pertussis transmission is lower than expected considering vaccine coverage levels. ...
Article
Measles and pertussis are ubiquitous vaccine-preventable diseases, which remain an important public health problem in developing countries. Hence, developing a deep understanding of their transmission dynamics remains imperative. To achieve this, we compared the impact of vaccination at both individual and population levels in a Senegalese rural community. This study represents the first such comparative study in tropical conditions and constitutes a point of comparison with other studies of disease dynamics in developed countries. Changes in the transmission rates of infections are reflected in their mean ages at infection and basic reproductive ratio calculated before and after vaccination. We explored persistence of both infections in relation to population size in each village and found the inter-epidemic period for the whole area using wavelets analysis. As predicted by epidemiological theory, we observed an increase in the mean age at infection and a decrease in the reproductive ratio of both diseases. We showed for both the pre- vaccination and vaccine eras that persistence depends on population size. After vaccination, persistence decreased and the inter-epidemic period increased. The observed changes suggest that vaccination against measles and pertussis induced a drop in their transmission. Similarities in disease dynamics to those of temperate regions such as England and Wales were also observed.
... Interestingly, it was not true. If anything children who survived measles had lower mortality than children who had not had measles infection [46,[48][49][50]. ...
... As measles vaccine obviously prevents measles deaths, there is only one solution to this enigma: children who contract measles have lower mortality following measles infection. This was entirely consistent with the follow-up studies showing lower mortality after measles infection [46,[48][49][50]. But then the mortality reduction after measles vaccine remains essentially unexplained. ...
Article
From a low-income country perspective, we need to emphasize factors which affect acquired susceptibility to severe infection. Such factors may lend themselves to modification by public health interventions. The present paper reviews the experience with understanding the causes of severe measles infection and the impact of health interventions in Guinea-Bissau over a 28-year period. In the 1970s, acquired susceptibility because of malnutrition was considered to be the main cause of high mortality. However, we found no association between nutritional status and subsequent risk of dying of measles. Instead, crowding and intensity of exposure were the main determinants of severe measles. Factors related to transmission have been substantiated for measles, chickenpox, whooping cough and polio. We found measles vaccination to be associated with a major reduction in mortality, particularly for girls. This suggested that measles vaccine has a beneficial nontargeted immune stimulatory effect. The importance of nontargeted effects was clearly documented when World Health Organization introduced a new high-titre measles vaccine (HTMV). HTMV was fully protective but associated with twofold higher mortality for girls. Bacille Calmette Guérin (BCG), diphtheria-tetanus-pertussis (DTP) and oral polio vaccine (OPV) have also shown nontargeted effects, the effect being beneficial for BCG and OPV but negative for DTP. Both beneficial and negative effects are strongest for girls. There are many acquired factors, which affect susceptibility to infection in ways which have not been explored by medical science. They may have a major impact on child survival in low-income countries.
... Though protective against measles infection, HTMV was associated with a two-fold increased female mortality compared with standard measles vaccine (MV) (5). In contrast, standard MV is associated with a reduction in mortality which is not explained by prevention of acute measles infection (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). This observation has been confirmed in the randomised or blinded studies of MV (3,9,10,21,22). ...
... Though protective against measles infection, HTMV was associated with a two-fold increased female mortality if the children got DTP after HTMV (5). In contrast, standard measles vaccine (MV) is associated with a reduction in mortality which is not explained by prevention of acute measles infection (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), and with reduced mortality for girls relative to boys (5,7,13,17,21-31); for example, the female-male mortality ratio (MRR) declined from approximately 1.00 to 0.65 after the first MV campaigns in two rural areas of Senegal (13,17). ...
... However, it has been demonstrated that high vaccination coverage does not imply that children are vaccinated according to the schedule [9][10][11][12][13][14][15][16]. Furthermore, vaccines can have non-specific effects on morbidity and mortality among children, particularly in high mortality areas [17][18][19]. These effects can be influenced by the timeliness of vaccination, with potential negative consequences of delayed vaccination [12,20,21]. ...
Article
To identify the determinants of timely vaccination among young children in the North-West of Burkina Faso. This study included 1665 children between 12 and 23 months of age from the Nouna Health and Demographic Surveillance System, born between September 2006 and December 2008. The effect of socio-demographic variables on timely adherence to the complete vaccination schedule was studied in multivariable ordinal logistic regression with 3 distinct endpoints: (i) complete timely adherence, (ii) failure, and (iii) missing vaccination. Three secondary endpoints were timely vaccination with BCG, Penta3, and measles, which were studied with standard multivariable logistic regression. Mothers' education, socio-economic status, season of birth, and area of residence were significantly associated with failure of timely adherence to the complete vaccination schedule. Year of birth, ethnicity, and the number of siblings was significantly related to timely vaccination with Penta3 but not with BCG or measles vaccination. Children living in rural areas were more likely to fail timely vaccination with BCG than urban children (OR=1.79, 95%CI=1.24-2.58 (proximity to health facility), OR=3.02, 95%CI=2.18-4.19 (long distance to health facility)). In contrast, when looking at Penta3 and measles vaccination, children living in rural areas were far less likely to have failed timely vaccinations than urban children. Mother's education positively influenced timely adherence to the vaccination schedule (OR=1.42, 95%CI 1.06-1.89). There was no effect of household size or the age of the mother. Additional health facilities and encouragement of women to give birth in these facilities could improve timely vaccination with BCG. Rural children had an advantage over the urban children in timely vaccination, which is probably attributable to outreach vaccination teams amongst other factors. As urban children rely on their mothers' own initiative to get vaccinated, urban mothers should be encouraged more strongly to get their children vaccinated in time.
... Administration of LAV to infants can elicit cellular immunity, as measured in vitro by MV-specific proliferation assays [4], and may benefit immunized infants [22,23]. Still, neutralizing antibody correlates most strongly with protection, and a MV vaccine that elicits protective antibody responses in young infants would contribute to eradication efforts and would decrease MV-associated mortality. ...
Article
Measles is associated with a million deaths a year in developing countries because of secondary infections. Morbidity is particularly severe in young infants. Both measles-induced immune suppression and atypical measles have been associated with a type 2 cytokine bias of the immune response. The role of individual virus proteins in the induction of these cytokine responses is unknown and could be important for the development of new vaccines. We have used a rhesus macaque model and DNA vaccines to investigate cytokine responses to the individual measles virus (MV) protective antigens, hemagglutinin and fusion. The hemagglutinin protein primed for a type 2 cytokine response, with suppression of interleukin (IL)-12 and preferential production of IL-4 after MV challenge. The fusion protein primed for a type 1 response with preferential production of interferon-γ. Responses were modulated when both proteins were used for priming. Therefore, the specific proteins included in a new measles vaccine will affect the type of cytokine response elicited
... In the available studies from Guinea-Bissau, Senegal and Bangladesh, after the acute phase of measles there was rather a trend for lower mortality infection than uninfected, unvaccinated controls (Table S2). Noteworthy, the lower mortality after measles infection was not a selection bias due to the frail children having died already of measles infection; the same trend of lower mortality after measles infection was found in situations with no acute measles mortality [28]. Hence, these studies suggested that measles infection could have a beneficial effect on survival and they refuted the hypothesis that the mortality reduction after MV was due to prevention of long-term excess mortality after measles infection. ...
Article
Background: Epidemiological and immunological studies are increasingly reporting non-specific effects (NSEs) of vaccines; i.e. vaccines may affect the risk and severity of non-targeted infections. We reviewed how epidemiological studies developed the concept of beneficial NSEs of live vaccines. Sources: This is a personal narrative of how we came to pursue the concept of NSEs in studies of measles vaccine (MV) from the late 1970s. We also searched Pubmed for epidemiological studies of nonspecific/non-specific effects (NSEs) of the most common human vaccines. Content: When smallpox vaccine was introduced around 1800, bacillus Calmette-Guérin (BCG) against tuberculosis in the 1920s and oral polio vaccine (OPV) in the 1960s, there were suggestions that these live attenuated vaccines reduced mortality more than expected. However, scientific follow-up was limited and the concept of beneficial NSEs did not become mainstream. We observed beneficial NSEs after MV was introduced in low-income countries in the 1970s. Subsequent observational studies and randomized trials confirmed beneficial NSEs of smallpox vaccine, BCG and OPV. Recently, beneficial NSEs have been claimed for the non-live diphtheria-tetanus-pertussis and rabies vaccines. However, no non-live vaccine has yet been documented to produce beneficial NSEs. Implications: Observational and experimental research has shown beneficial NSEs of four live attenuated vaccines: smallpox vaccine, BCG, OPV and MV. With immunological evidence now supporting the epidemiological observations, it is urgent to take both the specific and NSEs into account in the planning of vaccination programmes.
... 27 Furthermore, the only study linking measles antibody level to subsequent mortality found that lower measles antibody levels were associated with lower, not higher, mortality over the next 5 years. 28 The available data thus supports that if we could give early MV in presence of MatAb, it would not hamper measles control and it would lead to lower overall mortality. ...
Article
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Background: Early 2-dose measles vaccine (MV) at 4 and 9 months of age vs. the WHO strategy of MV at 9 months of age reduced all-cause child mortality in a previous trial. We aimed to test two hypotheses: 1) a 2-dose strategy reduces child mortality between 4 and 60 months of age by 30%; 2) receiving early MV at 4 months in the presence versus absence of maternal measles antibodies (MatAb) reduces child mortality by 35%. Methods: Single-centre open-label community-based randomised controlled trial in Guinea-Bissau, with 2:1 block-randomisation by sex to a 2-dose (4 + 9 months) vs. 1-dose (9 months) MV strategy. Healthy children were eligible 4 weeks after the 3rd diphtheria-tetanus-pertussis-containing vaccine. Before randomisation a blood sample was collected to determine MatAb level. The primary outcome was all-cause mortality. Hazard ratios (HR) were derived from Cox regression in the per protocol population. We tested for interactions with national campaigns with oral polio vaccine (C-OPV). Trial registration: NCT01486355. Findings: Between August 2011-April 17th 2015, 6,636 children were enroled, 6,598[n2-dose=4,397; n1-dose=2,201] were included in the analysis of the primary outcome, The HR(2-dose/1-dose) between 4 and 60 months was 1.38 (95%CI: 0.92-2.06) [deaths: n2-dose=90; n1-dose=33]. Before the 9-month MV and the HR(1-dose/no dose) was 0.94 (0.45-1.96) [deaths: n2-dose=21; n1-dose=11]. The HR(2-dose/1-dose) was 0.81 (0.29-2.22) for children, who received no C-OPV [deaths/children: n2-dose=10/2,801; n1-dose=6/1,365], and 4.73 (1.44-15.6) for children, who received C-OPV before and after enrolment (p for interaction=0.027) [deaths/children: n2-dose=27/1,602; n1-dose=3/837]. In the 2-dose group receiving early MV at 4 months, mortality was 50% (20-68%) lower for those vaccinated in the presence of MatAb vs. the absence of MatAb [deaths/children: nMatAb=51/3,132; nnoMatAb=31/1,028]. Interpretation: The main result contrasts with previous findings but may, though based on a small number of events, be explained by frequent OPV campaigns that reduced the mortality rate, but apparently interacted negatively with early MV. The beneficial non-specific effects of MV in the presence of MatAb should be investigated further. Funding: ERC, Danish National Research Foundation, the Danish Council for Development Research, Ministry of Foreign Affairs, Novo Nordisk Foundation, European Union and the Lundbeck Foundation.
... "The belief in persistent immune suppression was stimulated by increased mortality after high-titre measles vaccination." [8] Once natural measles was monitored long-term the knowledge changed. According to Aaby, "When measles infection is mild, clinical measles has no long-term excess mortality and may be associated with better overall survival than no clinical measles infection. ...
Article
The oft-parroted sound bite -" we need herd immunity" -implies that if ninety five percent of the population can become "immune" to a disease via vaccination, target immunity levels will be met and diseases will either be eradicated or controlled. This sound bite is the most commonly pulled weapon used by the vaccinators, only second to "smallpox and polio were eradicated by vaccination." "Herd immunity" is the trump card for the defense of vaccination on TV, Internet, medical journals and newspapers as to why we should be vaccinated over and over throughout our lives, with an ever-increasing number of vaccines. Paul Offit smiled and PLAYED THE CARD while peddling his book on the comedy central channel as Steven Colbert jokingly said, "if the vaccines work so good for you, why do I need one?" Dr. Mark Segal PULLED IT on fox news as Mary Holland, JD eloquently described the issue of vaccine injury and loss of legal recourse in an era of forced and mandated vaccines. In addition to flaunting several false allegations and sound bites, Dr. Segal's well-rehearsed rant brushed right over the issue at hand, the fact that victims of vaccine injury have no legal right to sue -and instead launched into his agenda of scaring the listeners by parroting the "herd immunity" dogma. The hype about herd immunity unfortunately creates a wall of hostility between those who vaccinate and those who delay some vaccines, avoid certain vaccines, or quit vaccinating altogether.
... However, this hypothesis was not supported by individual level data showing higher long-term mortality after measles infection. The studies which have examined long-term mortality have tended to find lower subsequent mortality if the individual survived the acute phase of measles infection (38,39). Hence, it may not be the prevention of immune amnesia which explains the beneficial effect of MV. ...
Article
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Background Measles vaccine (MV) administered as the last vaccine after the third dose of diphtheria-tetanus-pertussis (DTP) may be associated with better child survival unrelated to prevention of measles infection. Other studies have shown that MV administered after DTP was more beneficial and was associated with lower mortality compared with DTP administered after MV or DTP administered simultaneously with MV. We compared the difference in mortality between measles vaccinated after DTP3 and measles-unvaccinated children in Navrongo, Ghana.Methods This was a follow-up study involving annual cohort of children aged 9–23 months from 1996 to 2012. We assessed survival in relation to the measles vaccination status within the first 12 months from interview date and until 5 years of age using Cox proportional hazards models.ResultsIn all, 38,333 children were included in the study. The proportion of children vaccinated with MV-after-DTP3 increased from 45% in 1996 to 95% in 2012. The adjusted hazard ratio (HR) for measles unvaccinated compared with MV-after-DTP3 vaccinated children was 1.38 (1.15–1.66) in the first 12 months after assessment of vaccination status and 1.22 (1.05–1.41) with follow-up to 5 years of age. The national immunization days campaigns with oral polio vaccine or MV might have reduced the effect of being MV-after-DTP3 vaccinated vs MV-unvaccinated. For 12 months of follow-up, the HR before a campaign for MV-unvaccinated children was 1.63 (1.23–2.17) compared to those who received MV-after-DTP3. After the campaign, the HR reduced to 1.23 (0.97–1.54). Stratifying the analysis by sex, measles-unvaccinated boys had a HR of 1.69 (1.33–2.61) compared to measles-unvaccinated girls who had a HR 1.06 (0.79–1.40) during 1-year follow-up. In 1989, only 7% of children in the area had received MV-after-DTP3; the increase in MV-after-DTP3 coverage from 1989 to 2012 may have lowered mortality rate among children aged 9 months to 3 years by 24%.Conclusion Though an observational study, our findings suggest that measles vaccination, administered in the recommended sequence, is associated with improved child survival and may have contributed importantly to the mortality decline toward the achievement of Millennium Development Goal 4.
Article
Background: Randomised trials have shown that measles vaccine (MV) prevents non-measles deaths. MV-campaigns are conducted to eliminate measles infection.The overall mortality effect of MV-campaigns has not been studied. Methods: Bandim Health Project (BHP) surveys children aged 0-4 years in rural Guinea-Bissau through a health and demographic surveillance system. A nationalMV-campaign in 2006 targeted children aged 6 months-15 years. In a Cox proportional-hazards model with age as underlying time-scale we compared mortality for children aged 6-59 months after the campaign with mortality in the same age group during the two previous years. Results: 8158 children aged 6-59 months were under BHP surveillance during the 2006-campaign and 7999 and 8108 during similar periods in 2004 and 2005. At least 90% of the eligible children received MV in the campaign. There were 161 non-accident deaths in the 12 months after the campaign, compared with 203 and 206 deaths in the two previous years, the adjusted mortality rate ratio (aMRR) comparing all children in 2006 with all children in 2004-2005 being 0.80 (95%CI: 0.66-0.96).Censoring deaths due to measles infection the aMRR was 0.83 (0.69-1.00).The mortality reduction was separately significant for girls (aMRR=0.74 (0.56-0.97)) and for children who had also received routine MV (MRR=0.59 (0.36-0.99)). Conclusion: Mortality levels were stable during 2004 and 2005 but a significant drop occurred after the 2006 MV-campaign and was not explained by prevention of measles deaths. If MV-campaigns reduce non-measles related mortality the policies for measles vaccination should take this into account.
Article
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Measles vaccines (MV) have sex-differential effects on mortality not explained by protection against measles infection. The authors examined whether whole-cell diphtheria-tetanus-pertussis (DTP) vaccine has sex-differential and non-specific effects. DATA SOURCES AND ELIGIBILITY: Following previous reviews and a new search, the effect of DTP on mortality up to the next vaccination was assessed in all studies where DTP was given after BCG or DTP was given after MV and there was prospective follow-up after ascertainment of vaccination status. High-mortality countries in Africa and Asia. The initial observation of negative effect of DTP generated six hypotheses, which were examined in all available studies and two randomised trials reducing the time of exposure to DTP. Consistency between studies. In the first study, DTP had negative effects on survival in contrast to the beneficial effects of BCG and MV. This pattern was repeated in the six other studies available. Second, the two 'natural experiments' found significantly higher mortality for DTP-vaccinated compared with DTP-unvaccinated children. Third, the female-male mortality ratio was increased after DTP in all nine studies; in contrast, the ratio was decreased after BCG and MV in all studies. Fourth, the increased female mortality associated with high-titre measles vaccine was found only among children who had received DTP after high-titre measles vaccine. Fifth, in six randomised trials of early MV, female but not male mortality was increased if DTP was likely to be given after MV. Sixth, the mortality rate declined markedly for girls but not for boys when DTP-vaccinated children received MV. The authors reduced exposure to DTP as most recent vaccination by administering a live vaccine (MV and BCG) shortly after DTP. Both trials reduced child mortality. These observations are incompatible with DTP merely protecting against the targeted diseases. With herd immunity to whooping cough, DTP is associated with higher mortality for girls. Randomised studies of DTP are warranted to measure the true impact on survival.
Article
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Objective To examine the effect of the first introduction of measles vaccine (MV) in Guinea-Bissau in 1979. Setting Urban community study of the anthropometric status of all children under 6 years of age. Participants The study cohort included 1451 children in December 1978; 82% took part in the anthropometric survey. The cohort was followed for 2 years. Intervention In December 1979, the children were re-examined anthropometrically. The participating children, aged 6 months to 6 years, were offered MV if they did not have a history of measles infection. There were no routine vaccinations in 1979–1980. Primary and secondary outcome measures Age-adjusted mortality rate ratios (MRRs) for measles vaccinated and not vaccinated children; changes in nutritional status. Results The nutritional status deteriorated significantly from 1978 to 1979. Nonetheless, children who received MV at the December 1979 examination had significantly lower mortality in the following year (1980) compared with the children who had been present in the December 1978 examination but were not measles vaccinated. Among children still living in the community in December 1979, measles-vaccinated children aged 6–71 months had a mortality rate of 18/1000 person-years during the following year compared with 51/1000 person-years for absent children who were not measles vaccinated (MRR=0.30 (0.12–0.73)). The effect of MV was not explained by prevention of measles infection as the unvaccinated children did not die of measles infection. Conclusions MV may have beneficial non-specific effects on child survival not related to the prevention of measles infection.
In 1989, high-titer (HT) Edmonston-Zagreb measles vaccine with a titer more than 10(4.7) plaque-forming-units was recommended by the World Health Organization for use in areas with a high incidence of measles in children younger than 9 months. In 1992, the recommendation was rescinded following reports from Guinea-Bissau, Senegal, and Haiti showing an increased incidence of female mortality occurring after administration of HT Edmonston-Zagreb vaccination. We reviewed 9 studies of HT measles vaccines that reported data on mortality. These reports included 4 randomized trials comparing HT vaccine administered to children younger than 9 months with standard-titer (ST) vaccines (10(3.0) to 10(4.0) plaque-forming-units) given at 9 months of age. Five studies from Zaire, Haiti, Senegal, Rwanda, and Zaire had no control group receiving ST vaccine at 9 months of age, but investigators were able to examine the female-to-male mortality ratio within these HT studies. Investigators have hypothesized that HT vaccine had caused immune suppression similar to that of measles infection. The present review suggests first that the HT vaccine itself is unlikely to be the cause because the effect was not found in all studies. Second, the increased mortality started only after 9 to 10 months of age when controls received ST measles vaccine, and HT groups received the "control vaccine." It was not found in the studies that provided another measles vaccine instead of control vaccine. Third, because the HT studies with excess mortality rates showed increased female mortality rates, we need to find environmental or contextual conditions associated with increased female mortality rates in some studies to explain the problem associated with HT measles vaccination.
Article
Several studies have suggested that routine childhood immunisations may have non-specific effects on mortality. To examine which disease categories might be affected, we investigated whether immunisation status had an impact on the case fatality for hospitalised children. Between 1990 and 1996, the Bandim Health Project maintained a register of all children from the study area hospitalised at the paediatric ward of the central hospital in Bissau, Guinea-Bissau. The study included 2079 hospitalised children aged 1.5-17 months coming from the Bandim study area. Among children whose vaccination card had been seen at admission, the case fatality ratio for measles-vaccinated children versus measles-unvaccinated children was 0.51 (0.27-0.98), the beneficial effect being significantly stronger for girls than for boys (test of interaction, p=0.050). The protective effect of measles vaccine remained unchanged when hospitalised measles cases were excluded from the analysis (0.49 (0.26-0.94)). The effect of measles vaccine was strongest for children with pneumonia (MR=0.28 (0.07-0.91)) and presumptive malaria (MR=0.40 (0.13-1.18)). For measles-vaccinated children, the female to male case fatality ratio was 0.54 (0.28-0.97). Among children having received diphtheria-tetanus-pertussis (DTP) and oral polio (OPV) as the last vaccines, girls had higher case fatality than boys, the mortality ratio being 1.63 (1.03-2.59). The female to male ratios were significantly inversed for DTP and OPV versus measles vaccine (test of interaction, p=0.003). These results remained unchanged if 1-month post-discharge deaths were included in the analysis, and in multivariate analyses controlling for determinants of mortality. In conclusion, measles vaccine was associated with reduced mortality from diseases other than measles, the beneficial effect being stronger for girls than for boys. On the other hand, DTP and OPV vaccine were associated with higher case fatality for girls than for boys. Understanding the divergent non-specific effects of common vaccines may contribute to better child survival in developing countries.
Article
The safety and reactogenicity of a booster dose of GSK Biologicals' hexavalent DTPa-HBV-IPV/Hib vaccine (N=4725) was compared with the separate administration of GSK Biologicals' DTPa-IPV/Hib and HBV vaccines (N=4474) in two open, randomized multicenter studies (A and B). Solicited symptoms occurring within 4 days of vaccination were recorded on diary cards and serious adverse events (SAEs) were collected throughout the study period. In Study A (N=1149), incidences of solicited symptoms were similar in both groups; there were no SAEs either reported within 4 days of vaccination or considered to be causally related to vaccination. In study B (N=8050), where fever was the only solicited symptom, rectal temperature > or =39.5 degrees C was observed in 2.5% and 2.8% of the subjects, respectively. Fever > or =40.0 degrees C was rare (0.6%), and only two cases of febrile convulsions were recorded during the 4 days following vaccination both in the control group. Large swelling reactions (defined as local injection site swelling with diameter >50 mm, noticeable diffuse injection site swelling or noticeable increased circumference of the injected limb) were reported following 2.3% of the booster vaccine doses, regardless of the vaccine used. Extensive swelling reactions involving an adjacent joint were reported in 0.1% of the subjects. Two SAEs, both reported after booster doses of DTPa-IPV/Hib and HBV vaccines administered separately, were considered by the investigators to be related to vaccination. Both resolved completely without sequelae. The hexavalent DTPa-HBV-IPV/Hib vaccine and the DTPa-IPV/Hib and HBV vaccines administered separately have similar good reactogenicity and safety profiles when given as booster doses in the second year of life.
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To examine whether chickenpox in children below 2 years of age is associated with post-infection changes in growth, morbidity or mortality. An outbreak of chickenpox was investigated in Guinea-Bissau. An examination, interview and anthropometry were performed 6 months after the epidemic for a group of children and matched controls whose weight had been measured at the time of the chickenpox episode. All children diagnosed with chickenpox before 2 years of age were followed for survival and hospitalisations to the age of 3 years and compared with all other children in the community. At the 6-month follow-up, skin infections tended to be more frequent in cases (p<0.06) and more cases had used antibiotics within the last month (p<0.03). Although there had been no difference before chickenpox infection, girls with chickenpox infection had significantly higher weight, height and larger arm-circumferences than controls (all p<0.01). After chickenpox infection, the incidence of hospitalisation and long-term mortality was the same for cases and other children in the community (respectively, incidence rate ratio=1.16 (0.77-1.74) and mortality ratio=0.74 (0.39-1.41)). Though chickenpox may be associated with increased short-term morbidity, it does not appear to have any negative long-term effect on growth, severe morbidity and survival of young children.
Article
Introduction: Emerging evidence suggests that vaccines, in addition to their disease-specific effects, have important non-specific effects (NSEs), which contribute to their overall effect on mortality and morbidity. Immunological studies have shown that NSEs are biologically plausible. Many advocate that randomized controlled trials (RCTs) with overall mortality or morbidity as the outcome are the only way forward to confirm or refute NSEs. Areas covered: We discuss the limitations of using RCTs only as a tool to evaluate NSEs of vaccines. Such RCTs can be ethically problematic, they are time consuming and expensive. Furthermore, they only assess the NSEs in a given context, but it is inherent in the concept of NSEs that the NSEs of a given vaccine are modified by other immunomodulatory conditions. As an alternative, we propose that triangulation of RCTs and observational studies, merging multiple lines of evidence with different underlying bias structures, can build a strong argument for causality. We examine two examples related to measles vaccine and oral polio vaccine. Expert commentary: Using RCTs alone to evaluate NSEs of vaccines severely limits the possibilities for studying NSEs. Results from both RCTs and non-RCT studies should be triangulated to strengthen causal interpretation.
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When the bacillus Calmette-Guérin (BCG) vaccine was introduced in the 1920s, it was suggested that BCG occasionally had nonspecific beneficial effects on mortality beyond the specific protection against tuberculosis. Considering that BCG has since then become the most used vaccine in the world, surprisingly few studies have been undertaken into the effect of BCG on general mortality and morbidity. Recent studies suggest that BCG has beneficial nontargeted effects on general infant morbidity and mortality in low-income countries, often with the most pronounced effect among girls. These observational findings are supported by early trials in which children were randomized or alternated to BCG vaccination. Furthermore, a BCG scar and a positive tuberculin reaction are related to better survival among BCG-vaccinated children in low-income countries, especially for girls. The findings are not explained by frailty bias, in other words, that healthy children are more likely to receive BCG vaccination. A nonspecific, gender-differential effect of BCG on general infant mortality may have large implications for tuberculosis vaccine research and routine vaccination policy.
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Live vaccines including BCG and measles may have non-targeted beneficial effects on childhood survival in areas with high mortality. The authors therefore undertook a survey of vaccinia scars to evaluate subsequent mortality. Based on a population census, a cohort of 1893 adults in urban Guinea-Bissau was examined in 1998 and followed until 2002. All cause mortality, excluding accidents. The median age of vaccinia vaccinations had been 16-18 years. Adults with a vaccinia scar had a mortality ratio (MR) of 0.60 (0.41-0.87) compared to those without any scar. The effect was stronger for women. Mortality decreased with each additional vaccinia scar (MR=0.73 (0.56-0.95)). Among 502 individuals with information on HIV infection, the age-adjusted HIV-2 prevalence was 2.45 (1.06-5.65) for those with a vaccinia scar. Control for district, ethnic group, schooling, place of birth, quality of housing and HIV status had little effect on the estimate. Since vaccinia and BCG scars could have been confused, mortality for adults with vaccinia and/or BCG scar was compared to those without, the MR being 0.61 (0.41-0.89). Known cultural or socio-economic factors possibly associated with access to vaccination had no influence on the mortality ratio for having a vaccinia scar. Hence, vaccinia vaccination may have a prolonged beneficial effect on adult survival.
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The study aimed to investigate long-term consequences of respiratory syncytial virus (RSV) positive acute lower respiratory tract infection (ALRI) in a low-income country according to severity of the initial infection. The study was a 1:1 matched case-control study of 335 RSV case children and 335 control children. The mean age of RSV ALRI was 0.9 year and at follow-up, 6.8 years. Case children were identified at the hospital and in the community with an antigen and an IgM test to diagnose RSV. Severe RSV infection was defined when a child was treated at the hospital, whereas disease was assumed less severe when a child was diagnosed at home and received no care in the hospital. At follow-up, forced expiratory volume in 1 second (FEV1) and peak flow were significantly lower in case children (odds ratio [OR] = 0.28; 95% confidence interval [CI] 0.10-0.79), the effect being particularly marked for children with severe RSV. Bronchitis at follow-up was reported more frequently among the case children with severe disease. Fewer case children had a positive skin-prick test for local allergens than control children (OR 0.64; 95% CI = 0.44-0.94). Specific IgE for dust mites and cockroach was elevated (52%) in both case and control children. However, specific IgE to peppertree was higher in the case children (OR 2.18; 95% CI = 1.17-4.07). All identified differences were particularly marked for children with severe RSV. Severe RSV infection in infancy was associated with decreased lung function in preschool age in Guinea-Bissau. Children with severe RSV disease had more long-term health problems than children with less severe disease.
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To examine in a randomised trial whether a 25% difference in mortality exists between 4.5 months and 3 years of age for children given two standard doses of Edmonston-Zagreb measles vaccines at 4.5 and 9 months of age compared with those given one dose of measles vaccine at 9 months of age (current policy). Randomised controlled trial. The Bandim Health Project, Guinea-Bissau, which maintains a health and demographic surveillance system in an urban area. 6648 children aged 4.5 months of age who had received three doses of diphtheria-tetanus-pertussis vaccine at least four weeks before enrolment. A large proportion of the children (80%) had previously taken part in randomised trials of neonatal vitamin A supplementation. Children were randomised to receive Edmonston-Zagreb measles vaccine at 4.5 and 9 months of age (group A), no vaccine at 4.5 months and Edmonston-Zagreb measles vaccine at 9 months of age (group B), or no vaccine at 4.5 months and Schwarz measles vaccine at 9 months of age (group C). Main outcome measure Mortality rate ratio between 4.5 and 36 months of age for group A compared with groups B and C. Secondary outcomes tested the hypothesis that the beneficial effect was stronger in the 4.5 to 9 months age group, in girls, and in the dry season, but the study was not powered to test whether effects differed significantly between subgroups. In the intention to treat analysis of mortality between 4.5 and 36 months of age the mortality rate ratio of children who received two doses of Edmonston-Zagreb vaccine at 4.5 and 9 months of age compared with those who received a single dose of Edmonston-Zagreb vaccine or Schwarz vaccine at 9 months of age was 0.78 (95% confidence interval 0.59 to 1.05). In the analyses of secondary outcomes, the intention to treat mortality rate ratio was 0.67 (0.38 to 1.19) between 4.5 and 9 months and 0.83 (0.83 to 1.16) between 9 and 36 months of age. The effect on mortality between 4.5 and 36 months of age was significant for girls (intention to treat mortality rate ratio 0.64 (0.42 to 0.98)), although this was not significantly different from the effect in boys (0.95 (0.64 to 1.42)) (interaction test, P=0.18). The effect did not differ between the dry season and the rainy season. As neonatal vitamin A supplementation is not WHO policy, the analyses were done separately for the 3402 children who did not receive neonatal vitamin A. In these children, the two dose Edmonston-Zagreb measles vaccine schedule was associated with a significantly lower mortality between 4.5 and 36 months of age (intention to treat mortality rate ratio 0.59 (0.39 to 0.89)). The effect was again significant for girls but not statistically significant from the effect in boys. When measles cases were censored, the intention to treat mortality rate ratio was 0.65 (0.43 to 0.99). Although the overall effect did not reach statistical significance, the results may indicate that a two dose schedule with Edmonston-Zagreb measles vaccine given at 4.5 and 9 months of age has beneficial non-specific effects on children's survival, particularly for girls and for children who have not received neonatal vitamin A. This should be tested in future studies in different locations. Clinical trials NCT00168558.
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To examine whether the reduction in mortality after standard titre measles immunisation in developing countries can be explained simply by the prevention of acute measles and its long term consequences. An analysis of all studies comparing mortality of unimmunised children and children immunised with standard titre measles vaccine in developing countries. 10 cohort and two case-control studies from Bangladesh, Benin, Burundi, Guinea-Bissau, Haiti, Senegal, and Zaire. Protective efficacy of standard titre measles immunisation against all cause mortality. Extent to which difference in mortality between immunised and unimmunised children could be explained by prevention of measles disease. Protective efficacy against death after measles immunisation ranged from 30% to 86%. Efficacy was highest in the studies with short follow up and when children were immunised in infancy (range 44-100%). Vaccine efficacy against death was much greater than the proportion of deaths attributed to acute measles disease. In four studies from Guinea-Bissau, Senegal, and Burundi vaccine efficacy against death remained almost unchanged when cases of measles were excluded from the analysis. Diphtheria-tetanus-pertussis and polio vaccinations were not associated with reduction in mortality. These observations suggest that standard titre measles vaccine may confer a beneficial effect which is unrelated to the specific protection against measles disease.
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Objective: To examine the association between routine childhood vaccinations and survival among infants in Guinea-Bissau. Design: Follow up study. Participants: 15 351 women and their children born during 1990 and 1996. Setting: Rural Guinea-Bissau. Main outcome measures: Infant mortality over six months (between age 0-6 months and 7-13 months for BCG; diphtheria, tetanus, and pertussis; and polio vaccines and between 7-13 months and 14-20 months for measles vaccine). Results: Mortality was lower in the group vaccinated with any vaccine compared with those not vaccinated, the mortality ratio being 0.74 (95% confidence interval 0.53 to 1.03). After cluster, age, and other vaccines were adjusted for, BCG was associated with significantly lower mortality ratio (0.55 (0.36 to 0.85)). However, recipients of one dose of diphtheria, tetanus, and pertussis or polio vaccines had higher mortality than children who had received none of these vaccines (1.84 (1.10 to 3.10) for diphtheria, tetanus, and pertussis). Recipients of measles vaccine had a mortality ratio of 0.48 (0.27 to 0.87). When deaths from measles were excluded from the analysis the mortality ratio was 0.51 (0.28 to 0.95). Estimates were unchanged by controls for background factors. Conclusions: These trends are unlikely to be explained exclusively by selection biases since different vaccines were associated with opposite tendencies. Measles and BCG vaccines may have beneficial effects in addition to protection against measles and tuberculosis.
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In a rural area of Senegal, 1500 cases ofmeasles and 98 deaths (6.5%) were registered during a 4-year period (1983-1986). For children <5 years old, the acute case fatality ratio (CFR) was 9.6%. Compared with index cases who contracted measles in the village, secondary cases infected within the compound had a significantly higher mortality (odds ratio [OR], 2.9; 95% confidence interval [CI], 1.3-6.1). The CFR of secondary cases increased with the closeness of contact with the index cases; the ORs were 1.9 (CI, 0.6–6.0) for children living in the same compound but not the same household, 2.3 (CI, 1.0–5.7) for children living in the same household but not in the same hut, and 3.8 (CI, 1.7–8.4) for children living in the same hut. In large compounds with many cases, the CFR increased exponentially through the succession of generations; the ORs were 2.3 (CI, 1.0–5.2) in the second generation, 3.7 (CI, 1.1–3.0) in the third generation, 5.5 (CI, 1.7–18.1) in the fourth generation, and 16.1(C], 5.6–46.3) in the fifth or later generations. Postmeasles mortality through the year following measles infection was also significantly related to the intensity of exposure. Differences in exposure may bea major determinant of child survival, both at time of acute disease and for the long term impact of measles infection.
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Most global estimates indicate that more than 1 million children a year die from acute measles. The actual number of deaths may, however, be considerably higher than this. In addition, the impact of delayed mortality as a result of measles infection is only now being realized. Many months after they contract measles, children continue to experience higher levels of mortality and morbidity than those who do not. Immunization of children against measles therefore prevents mortality and morbidity not only during the acute phase but also during subsequent months. The impact of measles immunization programmes may therefore have generally been underestimated. The effects of measles infection on children during the early months of life are more damaging than those experienced by older children. Children should therefore be immunized against measles as early in life as possible, given the limitations of existing vaccines.
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Administration of high-titre measles vaccine (Edmonston-Zagreb (EZ) at > 10(5) plaque-forming units (PFU) per dose) before the age of 9 months has been recommended in areas with high measles mortality before the routine age of immunization after 9 months. The study compares the long-term survival after high-titre measles immunization at 5 months of age with that following routine immunization with standard-titre vaccine at 10 months of age. At 5 months of age the high-titre group received Edmonston-Zagreb (EZ-HT, 5 months) or Schwarz (SW-HT, 5 months) at titres > 10(5) PFU per dose, while the standard-titre group received placebo at 5 months of age and < 10(4) PFU per dose of Schwarz vaccine at 10 months (SW-std, 10 months). All the children were followed up to at least 36 months of age. The mortality ratio (MR) for infants in the EZ-HT, 5 months and SW-HT, 5 months groups was 1.32 (P = 0.089) and 1.45 (P = 0.092), respectively, which did not differ significantly from that of recipients of the SW-std, 10 months. The higher MR among recipients of the high-titre vaccines was due to the significantly lower survival among females compared with the females who received SW-std vaccine (EZ-HT, 5 months MR = 1.76, P = 0.013; SW-HT, 5 months MR = 2.14, P = 0.017). For children aged 5-10 months the high-titre measles vaccine did not increase mortality relative to unvaccinated children who had received placebo.
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Because measles immunization has been found in all studies to reduce mortality with more than the share of deaths attributed to acute measles, the authors examined mortality after measles infection in a study in a rural area of Senegal that included 6,924 unimmunized children, whom 1,118 developed measles. Age-adjusted post-measles mortality was similar to the mortality of unvaccinated, uninfected children (mortality ratio (MR) = 1.04, 95% confidence interval (CI) 0.80-1.35). When controlling for source of infection, mortality rate was significantly different for children who contracted measles from a person outside the home (index cases vs. unvaccinated, uninfected MR = 0.27, 95% CI 0.09-0.85) and for children infected at home (secondary cases vs. unvaccinated, uninfected MR = 1.10, 95% CI 0.80-1.51). Hence, secondary cases had markedly higher long-term mortality than did index cases (MR = 4.13, 95% CI 1.26-13.58). These estimates were essentially unchanged when the effects of season, period, separation from mother, size of community, and size of compound were investigated using a multivariate Cox regression model. The authors conclude that measles infection was not associated with increased mortality after the acute phase of infection and that index cases had lower mortality than uninfected, unvaccinated children. The reduction in mortality after measles immunization can therefore not be explained by the prevention of post-measles mortality.
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Data on measles incidence, acute case fatality, and delayed mortality were collected on 25,443 children aged 0-95 months during the course of a community-based, double-blind, placebo-controlled, randomized trial of vitamin A supplementation in rural, northern Ghana between 1989 and 1991. Measles vaccine coverage in these children was 48%. The overall estimated measles incidence rate was 24.3 per 1,000 child-years, and acute case fatality was 15.7%. There was not significantly increased mortality in survivors of the acute phase of measles compared with controls (rate ratio = 1.22, 95% confidence interval (CI) 0.65-2.30). Reported incidence rates and case fatality were higher in families with low paternal education, in the dry season, and in unvaccinated children, and case fatality was higher in malnourished children. There was no sex difference in incidence, but acute case fatality was somewhat higher in girls than boys (adjusted odds ratio = 1.3, 95% CI 0.9-2.1). Measles incidence was lower in vitamin A-supplemented groups (23.6 per 1,000 child-years) than in placebo groups (28.9 per 1,000 child-years), but this difference was not statistically significant (p = 0.33). Among 946 measles cases in clusters randomized to receive vitamin A or placebo, there was no marked difference in acute measles case fatality between vitamin A-supplemented and placebo groups (15.4% vs. 14.5%, respectively). The biologic effects of vitamin A supplemented on the subsequent clinical manifestations and severity of measles need further elucidation.
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Data obtained in animals indicate that neonatal immune responses are biased toward Th2. This could reduce the efficacy of vaccines against viral and mycobacterial diseases. The ability of human newborns to develop a Th1 immune response upon immunization has not been studied. Since the vaccine Mycobacterium bovis bacillus Calmette-Guérin (BCG) triggers a Th1-type response in adults, we investigated whether it induces a similar response in newborns and whether age at vaccination influences immunogenicity. We found that BCG vaccination at birth induces a memory Th1-type response of similar magnitude to that when given later in life. This study demonstrates that human newborns can be immunized against pathogens controlled by a Th1 immune response.
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Evidence suggests that both host and viral factors influence disease severity after infection with respiratory syncytial virus (RSV). To characterize the effects of pertussis toxin (PT) sensitization on subsequent RSV infection, BALB/c mice were treated with PT parenterally before RSV challenge. Priming with purified and detoxified PT before RSV challenge increased postchallenge weight loss and mortality. PT priming changed the kinetics, location, and composition of the cellular infiltrate in the lung but altered neither antibody responses nor virus titers. Passive transfer of PT-sensitized splenocytes produced similar responses. Priming with purified, but not genetically detoxified, PT propagated a modest type 2 cytokine response to RSV antigens. However, anti—interleukin-4 treatment before RSV challenge failed to abrogate the effects of PT priming. These data confirm that the preexisting immune environment can change virus-specific immunity and provide both a model for study of RSV disease and evidence that noninfectious immunomodulators may impact pathogen-specific immunity.
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Introduction. Survival distributions. Single sample nonparametric methods. Dependence on explanatory variables. Model formulation. The multiplicative log-linear hazards model. Partial likelihood. Several types of failure. Further problems. Exercises. Bibliography. Index.
Article
Objective: To examine the association between routine childhood vaccinations and survival among infants in Guinea-Bissau.Design: Follow up study.Participants: 15 351 women and their children born during 1990 and 1996.Setting: Rural Guinea-Bissau.Main outcome measures: Infant mortality over six months (between age 0-6 months and 7-13 months for BCG, diphtheria, tetanus, and pertussis, and polio vaccines and between 7-13 months and 14-20 months for measles vaccine).Results: Mortality was lower in the group vaccinated with any vaccine compared with those not vaccinated, the mortality ratio being 0.74 (95% confidence interval 0.53 to 1.03). After cluster, age, and other vaccines were adjusted for, BCG was associated with significantly lower mortality (0.55 (0.36 to 0.85)). However, recipients of one dose of diphtheria, tetanus, and pertussis or polio vaccines had higher mortality than children who had received none of these vaccines (1.84 (1.10 to 3.10) for diphtheria, tetanus, and pertussis). Recipients of measles vaccine had a mortality ratio of 0.48 (0.27 to 0.87). When deaths from measles were excluded from the analysis the mortality ratio was 0.51 (0.28 to 0.95). Estimates were unchanged by controls for background factors.Conclusions: These trends are unlikely to be explained exclusively by selection biases since different vaccines were associated with opposite tendencies. Measles and BCG vaccines may have beneficial effects in addition to protection against measles and tuberculosis.
Article
To study the kinetics of humoral as well as cellular immunity to measles and to test for associated immunosuppression 124 12 month old children were studied twice, before routine MMR and either 14, 22, 30, or 38 days after vaccination. Plaque reduction neutralization (PRN) titres were determined at these time points and lymphocytes were evaluated to identify changes in proportions of phenotype, their capacity to generate cytokines and to respond to blast transformation (BT) to measles hemagglutinin (HA), tetanus toxoid, and Candida antigen. The PRN titre and BT to HA plateaued at 30 days and CD8+ and NK cells increased after immunization. Interleukin 2, 4, and 10 showed no significant changes. There was mild suppression of BT at 14 and 22 days post-immunization. Interferon-γ was the principal cytokine produced after primary measles immunization, suggesting primary measles immunization induces predominantly a TH1 type response.
Article
The female/male mortality ratio among unimmunized children and children vaccinated with standard or high-titer measles vaccines was examined for all children born in the period 1985-1991 in a rural area of Senegal. The female/male mortality ratio from 9 months to 5 years of age for unvaccinated children was 0.94 (95% confidence interval (CI) 0.75-1.19), significantly different from the ratio of 0.64 (95% CI 0.48-0.85) for recipients of the Schwarz standard measles vaccine (p = 0.040). In the 4-year period, where high-titer measles vaccines were used in the study area, the female/male mortality ratio was 1.33 (95% CI 1.00-1.78) for recipients of high-titer Edmonston-Zagreb or Schwarz vaccines compared with 0.67 (95% CI 0.42-1.07) for recipients of the Schwarz standard vaccine (p = 0.013). Hence, the Schwarz standard and high-titer measles vaccines have divergent sex-specific effects on mortality throughout childhood. Further studies of the underlying mechanisms are needed.
Article
In an urban area of Guinea-Bissau, 71 children exposed to measles before age 6 months had a mortality risk of 34% (95% confidence interval (Cl) 24-47) between 6 and 60 months of age. The mortality risk for the 205 other children of the same birth cohort who had not been exposed to or developed measles was 11% (95% Cl 9-15), a significant difference compared with exposed children. With a version of the Cox regression model, maternal education was found to be the only background factor with a significant effect on mortality. When background factors were controlled for, the mortality of children exposed to measles was significantly higher than that of controls in each of the age intervals 6-11, 12-23, and 24-35 months. For the large subgroup of children of mothers without any formal education, exposed children had 5.7 times (95% Cl 2.7-12.0) higher mortality than did the control children in the age interval 6-35 months. Diarrhea deaths were particularly common among exposed children. Of 22 children who had been exposed before age 6 months during a subsequent epidemic and had a blood test taken, there was a significantly higher mortality risk (27%) between 6 months and 5 years than in the 26 controls who had a blood test (0%). Children who had elevated antibody titers to measles after exposure had a particularly high mortality compared with controls. These results suggest that later childhood mortality may be related to infectious experiences during the first months of life. The possible long-term health consequences of exposure to measles virus should be considered when assessing the value of measles control programs.
Article
When blood samples were analyzed for seroconversion after measles vaccination, it was discovered that the vaccine had been ineffective for a certain period. During the 2 years between vaccination and the time of seroanalysis, nonseroconverters had a significantly higher mortality than seroconverters (P less than 0.05). The incidence of measles among nonseroconverters was 30% during the period. Between 9 months and 3 years of age, cumulative mortality was 15.1% for nonseroconverters and 4.5% for seroconverters. The difference in mortality was larger when high risk groups (twins, motherless children) were excluded from the analysis (P less than 0.01). The difference in mortality was particularly marked among children vaccinated in the age group 9 to 11 months. This as well as other community studies suggest that measles vaccination reduces child mortality from the age of vaccination by at least 30%.
Article
Small-scale trials of the Edmonston-Zagreb (E-Z) measles vaccine were undertaken to determine the dose necessary to immunise 4-6-month-old infants. Antibody responses, measured 16 weeks after vaccination, were dose dependent: 40,000 plaque forming units given subcutaneously resulted in positive responses in all infants and higher antibody levels than doses of 20,000 or 10,000 units (10,000 units gave a failure rate of 25%). In further trials the E-Z vaccine was compared with the Schwarz vaccine, both being given in subcutaneous doses of 40,000 plaque forming units. In infants aged 20 weeks the E-Z vaccine produced higher levels of measles antibody and in those aged 18 weeks its superiority showed in a lower proportion failing to respond (3 of 39 versus 19 of 35).
Article
Clemens, J. D. (Center for Vaccine Development, U. of Maryland School of Medicine, Baltimore, MD 21201), B. F. Stanton, J. Chakraborty, S. Chowdhury, M. R. Rao, M. AH, S. Zimicki, and B. Wojtyniak. Measles vaccination and childhood mortality in rural Bangladesh. Am J Epidemiol 1988; 128; 1330–9. To ascertain whether measles vaccination was associated with reduced mortality rates in rural Bangladeshi children, the authors conducted a case-control study in four contiguous areas, two of which had participated in an intensive measles vaccination program which began in the spring of 1982. Cases were 536 children who had died in the four-area region at the age of 10–60 months between April 1982 and December 1984. Two age- and sex-matched controls were selected from the four-area region for each case; each control had survived at least through the date of death of the matched case. Measles vaccination was associated with a 36% (95% confidence interval 21%–48%) proportionate reduction in the overall rate of death and a 57% (95% confidence interval 43%–67%) reduction in the rate of deaths directly attributed to measles or ascribed to diarrhea, respiratory illness, or malnutrition. The association of measles vaccination and reduced mortality remained unchanged after the authors restricted controls to children who had survived at least one year after the deaths of their matched cases. Moreover, children vaccinated in 1982 exhibited a sustained reduction in the rate of death in 1983 and 1984. The authors concluded that measles vaccination was associated with a pronounced and sustained reduction in the rate of death among children in this study.
Article
Measles mortality and measles vaccine efficacy were determined during outbreaks in three Gambian villages. There were 146 cases of measles among 1073 children younger than 11 years. 30% of the children had been vaccinated against measles. The attack rate in unvaccinated children aged 9-47 months was 43% compared with 6% for children of the same age with documented measles vaccination. Vaccine efficacy was 37% for children vaccinated at 6-8 months of age and 89% for children vaccinated at 9 months or older. 5% of measles cases died before the initial investigation of the outbreaks and a further 10% of cases died during the ensuing 9 months. Only 1% of children who did not contract measles died in the 9 months after the outbreaks. Case-fatality rates were highest for measles patients less than 1 year old (64%) and fell with age. Measles remains a significant source of acute and delayed mortality in unvaccinated African populations.
Article
Earlier studies have suggested that general measles vaccination programmes should not be made a priority in developing countries because the presumably malnourished children saved from measles are likely to die from something else. Recent community studies indicate, however, that malnutrition is not the cause of high measles mortality. In an urban community in Guinea-Bissau, child mortality has been registered for a period of 3 years; 1 year before and 2 years after the introduction of a general measles vaccination program. In the years following the introduction of measles vaccination, mortality for children aged 6 to 35 months has significantly diminished. Though this is not a controlled study of vaccinated and unvaccinated children, much of the reduced mortality can apparently be attributed to the protective effect of measles vaccination. Children with a history of earlier measles infection had a significantly higher mortality rate than children vaccinated against measles. Rather than being a mechanism of natural selection taking the weakest children, measles apparently aggravates the condition of many children, leading to delayed excess mortality. In areas where the case fatality rate is high, vaccination against measles should be made an indispensable part of primary health care.
Article
During a measles vaccine trial in a rural area of Senegal, antibody status was examined within 10 days of exposure for 228 previously vaccinated and 313 unvaccinated children more than 12 months old who were exposed to measles at home. Thirty-six percent of the children developed clinical measles, the clinical diagnosis being confirmed for 135 of the 137 children from whom 2 blood samples were collected. Vaccine efficacy was 90% (95% confidence interval, 83 to 94%). The hemagglutinin-inhibiting antibodies (HI) or plaque neutralizing antibodies (PN) assays were equally efficient in predicting susceptibility and protection against measles. Vaccinated children who had no detectable HI or PN antibodies at exposure had significant protection against measles compared with seronegative unvaccinated children (HI vaccine efficacy, 49% (95% confidence interval, 21 to 68%); PN vaccine efficacy, 43% (95% confidence interval, 12 to 62%)). The attack rate was high for children with a titer of 40 to 125 mIU) 67% (4 of 6) of those with a positive hemagglutinin-inhibiting antibody test and 36% (13 of 36) of those with a positive PN test developed measles. Attack rates among children with HI or PN titers above 125 mIU were 2% (6 of 295) and 3% (7 of 258), respectively. Because titers of < or = 120 mIU have been found to offer little protection in another study, this antibody level may be the best screening value for assessing susceptibility and protection against measles. However, it should be noted that many seronegative vaccinated children are protected against measles infection.
Article
Chen R T (National Immunization Program (MS-E61), Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333, USA), Weierbach R, Bisoffi Z, Cutts F, Rhodes P, Ramaroson S, Ntembagara C and Bizimana F. A ‘post-honeymoon period’ measles outbreak in Muyinga sector, Burundi. International Journal of Epidemiology 1994; 23: 185–193. In Muyinga sector, Burundi, an area with good vaccination levels against measles and recent low incidence of measles, a major outbreak of measles in 1988 raised questions about the efficacy of the immunization programme. To help answer these questions, we 1) reviewed programme data on doses of measles vaccine administered, vaccine coverage, and measles incidence, and 2) conducted a census of the affected area to examine vaccine efficacy and measles mortality. We found that between 1980 and 1988 in Burundi, 1) measles vaccine coverage by age 1 had increased from 0% to 55%, 2) the incidence of reported measles cases declined from 12.1/1000 to 6.2/1000, 3) reported measles mortality dropped from 0.18/1000 to 0.08/1000, and 4) the interepidemic period had increased from 25 to 35 months. In the census, the best estimate of measles vaccine efficacy administered at 9 months of age was 73%. Measles increased the risk of death by 2.5-fold with the effect limited to the first month after measles. This outbreak demonstrated the ‘post-honeymoon period’ epidemic predicted by mathematical models in which outbreaks occur among accumulated susceptibles in a partially immunized population. Understanding this phenomenon is important in providing a basis for improved strategies of measles control. Such outbreaks present new challenges to newly maturing immunization pro grammes in improving skills in surveillance, outbreak investigation, and public relations.
Article
Immunization with high-titer measles vaccines has been associated with excess mortality in children 2–4 years after vaccination. In this study, immunologic parameters in 64 Peruvian children who had been immunized an average of 27 months earlier with high-titer vaccines were compared with parameters in 76 recipients of low-titer vaccines. Delayed-type hypersensitivity, lymphocyte phenotype distributions by flow cytometry, and lymphoproliferation after phytohemagglutinin (PHA) stimulation were assessed. High-titer recipients had smaller indurations to tetanus, diphtheria, and Proteus (P < .05) antigens, decreased PHA stimulation (P = .04), and a lower percentage of CD4+ lymphocytes (P = .04) than low-titer recipients. After adjustment for sex, concurrent illnesses, and other variables in regression analyses, high-titer recipients had a lower percentage of CD4+ lymphocytes (P = .025) and decreased lymphocyte proliferation to PHA (P = .058). These results may provide a clue to the pathogenesis of delayed excess mortality after high-titer measles vaccination in some developing countries.
Article
Defining the mechanism for the vaccine-enhanced illness associated with respiratory syncytial virus (RSV) is critical for advancing RSV vaccine development. Previous studies in which infants were vaccinated with formalin-inactivated alum-precipitated whole virus did not protect from RSV infection, and those infected had a high incidence of severe illness. In contrast, previous clinical trials evaluating live attenuated RSV showed no associated vaccine-enhanced illness. We have used a mouse model to explore the immunopathogenesis of RSV infection. In this study cytokine mRNA expression was examined using 32P-labeled oligonucleotide probes in Northern blot analyses of polyA RNA extracted from lungs of mice primed with various vaccine preparations then challenged nasally with live RSV. We have shown that upon challenge, priming of mice with inactivated virus or subunit F glycoprotein induced a pattern of cytokine mRNA expression suggesting a dominant Th2-like lymphocyte response (relative increase in IL-4 mRNA expression). In contrast, challenge of mice primed with live RSV by parenteral or mucosal routes induced a Th1-like pattern of cytokine mRNA expression (relative decrease in IL-4 mRNA expression compared to IFN-gamma mRNA expression). Thus, the formulation and route of delivery of vaccine products can influence the pattern of cytokine expression in lung upon RSV challenge.
Article
The mechanisms underlying the profound suppression of cell-mediated immunity (CMI) accompanying measles are unclear. Interleukin-12 (IL-12), derived principally from monocytes and macrophages, is critical for the generation of CMI. Measles virus (MV) infection of primary human monocytes specifically down-regulated IL-12 production. Cross-linking of CD46, a complement regulatory protein that is the cellular receptor for MV, with antibody or with the complement activation product C3b similarly inhibited monocyte IL-12 production, providing a plausible mechanism for MV-induced immunosuppression. CD46 provides a regulatory link between the complement system and cellular immune responses.
Article
Because measles immunization is reducing overall childhood mortality in addition to mortality from acute measles infection, it has been suggested that postmeasles cases have excess mortality, possibly related to persistent immunosuppression after measles infection. After an epidemic in 1988 in Guinea-Bissau, we therefore examined T lymphocyte subsets and long term survival among measles cases and controls. We examined 69 children < 3 years of age with a median delay of 2 months after measles infection and 71 controls who did not contract measles. The immunoalkaline method was used to determine T lymphocyte subsets. The children were followed for 5 years. Compared with controls, there were no significant differences in white blood cell count, absolute lymphocyte count, CD4 percentage, CD8 percentage, total CD4 count and total CD8 count, although measles cases examined > 2 months after infection had slightly higher CD4 counts than controls (P = 0.06). Adjusted for age, sex and immunization status, postmeasles cases had a mortality rate ratio of 0.50 (95% confidence interval, 0.22 to 1.16) (P = 0.11) compared with controls. There is no indication of persistent suppression of T cell subsets after measles infection, and postmeasles cases did not have higher mortality than uninfected community controls.
Article
We investigated the changes in intracellular cytokine levels in different lymphocyte populations induced by measles virus (MV). MV-infected and uninfected peripheral blood mononuclear cells were cultured with phorbol 2-myristate 13-acetate plus ionomycin in the presence of monensin for 10 hr. Surface antigen and intracellular cytokines, interleukin (IL)-2, interferon (IFN)-gamma, and IL-4, were stained simultaneously and analyzed by flow cytometry. The percentage of cells that expressed IL-2 and IFN-gamma was significantly increased in MV-infected CD3+, CD4+, and CD8+ lymphocytes and alphabeta T lymphocytes compared with that in uninfected lymphocytes. In gammadelta T lymphocytes, expression of IFN-gamma, not IL-2, was increased in MV-infected cells compared with that in uninfected cells. IL-2 was increased mainly in MV-infected CD4+ lymphocytes and alphabeta T lymphocytes, whereas IFN-gamma was increased mainly in MV-infected CD8+ lymphocytes and gammadelta T lymphocytes. Expression of IL-4 was unaffected by MV infection. These results demonstrate that MV enhances intracellular levels of type 1 cytokines during the acute phase of measles.
Article
A randomized, double-blind trial comparing a diphtheria-tetanus-acellular pertussis vaccine (DTaP) (pertussis toxoid and filamentous hemagglutinin) with a whole-cell vaccine (DTwP) was conducted. A case-contact study was nested in the trial to estimate absolute efficacy. From 1990 through 1994, 4181 children were randomized to receive one of the vaccines at 2, 4, and 6 months. Severe adverse events were monitored weekly during two visits after vaccination. Fewer serious adverse events were observed after DTaP. Surveillance for cough illnesses persisting more than 7 days, in children under 15 years of age, was made by weekly home visits. Examining physicians, blind to vaccination status, took samples for culture and serologic testing. Pertussis was defined as 21 or more days of cough confirmed by culture, serology, or contact with a culture-confirmed person. Beginning 28 days after the third vaccine dose, the overall ratio of pertussis incidence in the DTaP group relative to the DTwP group (RRac/wc) was 1.54 (95% CI, 1.23-1.93). In children younger than 18 months of age, RRac/wc was 1.16 (95% CI, 0.77-1.73) and 1.76 (95% CI, 1.33-2.33) in children older than 18 months, which suggests a shorter duration of protection with the acellular vaccine (P = 0.090). Absolute efficacy estimates derived from the case-contact study confirmed the lower protection afforded by the acellular vaccine compared with the whole-cell vaccine: 31% (95% CI, 7-49) versus 55% against the protocol case definition, and 85% (95% CI, 66-93) versus 96% for the more severe WHO case definition. Although vaccination with DTaP provided a lower degree of protection than the highly effective DTwP, this difference was less prominent before 18 months of age, the customary age for a fourth dose. The safer DTaP vaccine may prove a valuable substitute for whole-cell vaccines when used in a schedule that includes a booster-dose.
Article
To investigate the possibility of long-term suppression of T-lymphocyte subsets, we examined children exposed to measles at home during an epidemic in rural Senegal, at time of exposure and 1 and 6 months later. The measles case fatality ratio was 1%. Subclinical measles was common among vaccinated children exposed to measles (45%). Both clinical and subclinical cases of measles showed a significant rise in absolute CD4 count in the incubation period. In the prodromal phase and the first week after the rash, the lymphocyte percentage, the white blood cell count and the absolute CD4 cell numbers were significantly reduced. There was no persistent decrease of absolute CD4 or CD8 numbers at 1 or 6 months after exposure. Measles infection was followed by significant changes in the subset composition, both CD4 and CD8 percentages being significantly higher in the second month after measles than among non-seroresponders. These changes were more marked among girls, since they had significantly higher CD4 percentages and CD4/CD8 ratios than boys in the convalescence phase. In conclusion, measles infection is not associated with a long-term suppression of CD4+ or CD8+ T-lymphocytes.
Article
Despite a high coverage with measles vaccines in parts of west Africa, epidemics of measles occur with reduced severity in an increasing proportion of older children who have been vaccinated. We examined the effect of exposure to natural measles on immunity in vaccinated children. Our study was carried out in 1992 during an epidemic of measles in Niakhar, a rural area of Senegal with about 27,000 inhabitants who mostly live in compounds that include several households; within each household people live in different huts. Vaccine coverage in Niakhar was 81% at the time of our study. We measured haemagglutinin-inhibiting antibody at exposure and twice thereafter (after 4-5 weeks and at 6 months) in 36 vaccinated and 87 unvaccinated children. The frequency of measles and subclinical measles--defined as a four-fold or greater rise in antibody titre without clinical signs or symptoms--was related to intensity of exposure according to whether the index case was in the same hut, household, or compound. Clinical measles occurred in 20 (56%) of 36 unvaccinated children and in one (1%) of 87 vaccinated children. Subclinical measles occurred in 39 (45%) of 86 vaccinated children who were exposed to measles and in four (25%) of 16 unvaccinated children. The frequency was inversely related to pre-exposure antibody concentration (p<0.001 for trend) and directly related to intensity of exposure (p=0.002 for trend). Antibody concentrations in subclinical cases increased on average by 45-fold and remained raised for at least 6 months. Increased antibody titre after subclinical measles may be common in vaccinated children in West Africa where the intensity of exposure is high. As measles vaccination coverage increases, the circulation of wild measles will decrease, and vaccine-induced antibody is less likely to be boosted. Thus, new epidemics, albeit milder in form, may occur in vaccinated areas which should be recognised in campaigns to eradicate measles.
Article
Immunization with live influenza virus expands Th1 memory cells and facilitates more rapid recovery after heterosubtypic virus challenge. Immunization with inactivated virus generates a Th2 response and does not lead to heterosubtypic immunity. Creation of a Th1 priming environment by the inclusion of interleukin (IL)-12 with antibodies to IL-4 converted the response against inactivated virus to a Th1 response that was able to facilitate virus clearance upon heterosubtypic virus challenge. Evaluation of memory responses of mice immunized by the various protocols demonstrated that the type of immunization imprints T cell memory, dictating the nature of the response to subsequent infection. After live virus challenge, expansion of Th1 cells seems to facilitate the generation of cytotoxic T lymphocytes from naïve precursors. This latter finding may be the mechanism by which inactivated virus immunization in a Th1 cytokine context mediates heterosubtypic immunity.
Article
T helper type 1 (Th1) lymphocytes secrete secrete interleukin (IL)-2, interferon-γ, and lymphotoxin-α and stimulate type 1 immunity, which is characterized by intense phagocytic activity. Conversely, Th2 cells secrete IL-4, IL-5, IL-9, IL-10, and IL-13 and stimulate type 2 immunity, which is characterized by high antibody titers. Type 1 and type 2 immunity are not strictly synonymous with cell-mediated and humoral immunity, because Th1 cells also stimulate moderate levels of antibody production, whereas Th2 cells actively suppress phagocytosis. For most infections, save those caused by large eukaryotic pathogens, type 1 immunity is protective, whereas type 2 responses assist with the resolution of cell-mediated inflammation. Severe systemic stress, immunosuppression, or overwhelming microbial inoculation causes the immune system to mount a type 2 response to an infection normally controlled by type 1 immunity. In such cases, administration of antimicrobial chemotherapy and exogenous cytokines restores systemic balance, which allows successful immune responses to clear the infection.
Article
Immunization during the neonatal period often results in Th2-biased secondary responses. To understand the regulation of this phenomenon, we have examined all phases of Th development, from the generation of primary effectors to the duration of the primary effector stage to the production of memory effector function. First, we had previously reported that although primary responses in the neonatal lymph nodes are mature, mixed Th1/Th2-like, primary responses in the spleens of the same animals are exclusively Th2-like. To determine whether Th2-dominant secondary responses are due to the Th2-polarized primary function in the spleen, neonates were splenectomized before immunization. Even in the absence of primary neonatal splenic responses, the secondary responses of neonates were Th2 dominant. Thus, the overwhelmingly Th2 primary responses in the neonatal spleen are not required to generate Th2-dominant memory in the lymph nodes. Second, we have compared the kinetics of the primary response phase in neonates and adults. In adults, Ag-specific Th2 function disappeared rapidly from both the lymph nodes and spleen. In contrast, primary Th2 function persisted out to 5 wk in both neonatal organs. Third, the generation of Th memory responses was examined in animals initially immunized as neonates and in adults. These experiments demonstrated that neonates are selectively impaired in the development of Th1 memory effector function. Together, these results indicate that neonates are biased to Th2 function at all phases of an immune response.
Article
Measles still causes high mortality in children younger than 1 year of age. Administration of high titre measles vaccines before 7 months of age led to increased overall mortality, raising questions as to the immunological effects of measles vaccine in young infants. We investigated the immune response to standard titre vaccines given to children in Bangladesh in a single dose at age 9 months, or two doses at 6 and 9 months. Of the children vaccinated at age 9 months, 95% serocoverted, compared with 70% at age 6 months. Delayed-type-hypersensitivity reactions to candida antigen were significantly reduced in both vaccine groups at 6 weeks post-vaccination, but responses to other recall antigens studied were not significantly different from controls. In both vaccine groups, peripheral blood lymphocytes isolated at 6 and 24 weeks after vaccination showed significantly higher expression of activation markers upon in vitro stimulation, and a sustained increase in IL-2 production. These findings suggest prolonged immune activation after measles vaccination at the same time as some reduction in delayed hypersensitivity responses. Further study of the clinical effects of these changes is warranted.
Relative efficacy and safety of a two-component acellular pertussis vaccine with respect to a whole cell vaccine in rural Senegal
  • F Simondon
  • Preziosi Mp
  • A Yam
  • Ndiaye
  • Dia M Ehm
Simondon F, Preziosi MP, Yam A, Ndiaye EHM, Dia M, Kane C, et al. Relative efficacy and safety of a two-component acellular pertussis vaccine with respect to a whole cell vaccine in rural Senegal. Vaccine 1997;15:1606–12.
Non-specific effects of measles immunization and measles infection: a reanalysis of data from rural Bangladesh
  • P Aaby
  • A Bhuyia
  • L Nahar
  • K Knudsen
  • A Francisco
  • M Strong
Aaby P, Bhuyia A, Nahar L, Knudsen K, Francisco A, Strong M, et al. Non-specific effects of measles immunization and measles infection: a reanalysis of data from rural Bangladesh. Int J Epidemiol (revision).
Population et santé à Niakhar
  • A Chahnazarian
  • C Becker
  • V Delaunay
  • M P Préziosi
  • B Samb
  • F Simondon
Measles immunization research
  • Aaby
Newborns develop a T helper 1 type response to BCG vaccination
  • Marchant
Relative efficacy and safety of a two-component acellular pertussis vaccine with respect to a whole cell vaccine in rural Senegal
  • Simondon