Sex-associated differences in the antibody-dependent cellular cytotoxicity antibody response to measles vaccines.

Atabani,-S; Landucci,-G; Steward,-M-W; Whittle,-H; Tilles,-J-G; Forthal,-D-N

Clin-Diagn-Lab-Immunol. 2000 Jan; 7(1): 111-3

Clinical-and-diagnostic-laboratory-immunology

In some countries, excessive non-measles-related mortality has been observed among female recipients of high-titer measles vaccines. We determined if differences in the immune response to measles vaccines underlie the excessive female mortality by measuring the measles virus (MV)-specific antibody-dependent cellular cytotoxicity (ADCC) antibody response in 65 3-year-old Gambian children immunized with Edmonston-Zagreb medium-titer (EZ) or Schwarz standard vaccines during infancy. Among the 20 females and 22 males with undetectable anti-MV antibodies at the time of immunization, females had significantly lower ADCC than males (median cytotoxicities of 1/100 serum dilutions = 8.4 and 12%, respectively; P = 0.04). This sex-associated difference was present only among the six female and seven male recipients of EZ vaccine (median cytotoxicities = 5.1 and 19.0%, respectively; P = 0.02). There were no significant sex-associated differences in neutralizing antibody activity. Decreased ADCC antibody activity may contribute to the lower survival rate observed in females receiving high-titer measles vaccination.

 

Gender differences in the reactogenicity of measles-mumps-rubella vaccine.

Shohat,-T; Green,-M-S; Nakar,-O; Ballin,-A; Duvdevani,-P; Cohen,-A; Shohat,-M

Isr-Med-Assoc-J. 2000 Mar; 2(3): 192-5

Israel-Medical-Association-journal,-The

BACKGROUND: In trials comparing different formulations of measles vaccine, excess non-specific mortality occurred in female children who received high titer vaccine. These findings suggest a gender-specific effect of measles vaccine. OBJECTIVES: To determine whether gender differences exist in the rates of adverse reactions and morbidity in the month following immunization with measles-containing vaccine, and to evaluate whether there is a gender-specific association between the humoral immune response to measles vaccination and post-vaccination morbidity. METHODS: Parents completed questionnaires on the health status of 755 infants aged 15-20 months, during the month preceding and the month following the measles-mumps-rubella vaccination. Blood samples were tested for measles antibody titers in a subsample of 237 infants. RESULTS: After controlling background morbidity in the infants, the relative risk of fever and rash following vaccination was 2.35 in females and 1.36 in males. The geometric mean antibody titers against measles were similar in both sexes and there was no significant association between antibody titer and post-vaccination morbidity in either sex. CONCLUSIONS: Our findings demonstrate higher rates of adverse effects in females following vaccination with MMR vaccine, irrespective of the humoral response. This study emphasizes the need to consider possible gender differences when evaluating new vaccines.

 

Child mortality following standard, medium or high titre measles immunization in West Africa.

Knudsen,-K-M; Aaby,-P; Whittle,-H; Rowe,-M; Samb,-B; Simondon,-F; Sterne,-J; Fine,-P

Int-J-Epidemiol. 1996 Jun; 25(3): 665-73

International-journal-of-epidemiology

BACKGROUND. The World Health Organization (WHO) recommended the use of high titre measles vaccine in 1989. Subsequent long term follow-up of several trials yielded results suggesting higher mortality among children inoculated with medium and high titre vaccines compared to standard titre vaccines, although none of the individual trials found significant differences in mortality. METHODS. Long term survival after standard, medium and high titre measles vaccines has been investigated in a combined analysis of all West African trials with mortality data. In trials from Guinea-Bissau, The Gambia and Senegal, children received medium or high titre vaccines from 4 months of age and were compared to control groups recruited at the same time later receiving standard titre vaccine from 9 months of age. All children were followed up to at least 3 years old. RESULTS. Combining trials of high titre vaccines showed higher mortality among the high titre group compared to the standard group: mortality ratio (MR) = 1.33 (95% CI : 1.02-1. 73). Mortality among recipients of medium titre vaccines was not different from that in the standard vaccine group, MR = 1.11 (95% CI: 0.54-2.27). In a combined analysis by sex, the adjusted mortality ratios comparing high titre vaccine with standard vaccine were 1.86 (95% CI : 1.28-2.70) for females and 0.91 (95% CI : 0.61-1.35) for males. The trials were not designed to study long term mortality. Adjustments for several possible sources of bias did not alter the results. CONCLUSIONS. The combined analysis showed a decreased survival related to high titre measles vaccine compared with standard titre vaccines, though solely among females. As a result of these studies from West Africa and a study from Haiti, WHO has recommended that high titre measles vaccine no longer be used.

 

Long-term survival in trial of medium-titre Edmonston-Zagreb measles vaccine in Guinea-Bissau: five-year follow-up.

Aaby,-P; Lisse,-I-M; Whittle,-H; Knudsen,-K; Thaarup,-J; Poulsen,-A; Sodemann,-M; Jakobsen,-M; Brink,-L; Gansted,-U; et-al.

Epidemiol-Infect. 1994 Apr; 112(2): 413-20

Epidemiology-and-infection

A trial of protective efficacy which compared medium-titre Edmonston-Zagreb (EZ) measles vaccine (10(4.6) p.f.u.) from the age of 4 months with the standard Schwarz (SW) measles vaccine given from the age of 9 months was started in an urban community in Guinea-Bissau in 1985. Because trials of high-titre measles vaccine have found increased mortality among female recipients, we examined whether EZ medium-titre vaccine was associated with any long-term impact on mortality, suppression of T-cells, or growth. The mortality rate ratio over 5 years of follow-up was 1.12 for EZ children compared with children in the standard group (P = 0.63). Seventy-five percent of the children still residing in the area at 5 years of age took part in an immunological and anthropometric examination. There was no difference in T-cell subsets between the two groups. There was no difference in mid-upper-arm circumference, but EZ children were significantly shorter than the children in the standard group. In conclusion, medium-titre EZ was not associated with reduced survival or persistent immunosuppression.

 

Long term impact of high titer Edmonston-Zagreb measles vaccine on T lymphocyte subsets.

Lisse,-I-M; Aaby,-P; Knudsen,-K; Whittle,-H; Andersen,-H

Pediatr-Infect-Dis-J. 1994 Feb; 13(2): 109-12

Pediatric-infectious-disease-journal,-The

Several trials of high titer measles vaccine (> 10(4.7) plaque-forming unit) have found female recipients of Edmonston-Zagreb (EZ) vaccine to have lower survival than female recipients of standard measles vaccine. Two trials with medium and high titer EZ vaccine from the age of 4 months were conducted in Guinea-Bissau. To test for possible long term impact on the immune system, an investigation of T cell subsets was conducted among all children still residing in the community at 3 to 5 years of age. No differences were found between recipients of medium titer vaccine and controls. In the second trial, however, recipients of high titer had lower CD4:CD8 ratios than controls and had significantly higher CD8 percentages and lower CD4:CD8 ratios than recipients of medium titer EZ. When analyzed by sex, differences were found only among the girls. However, these differences were small and seemed unlikely to explain the reduced survival which has been associated with high titer EZ measles vaccination. In the 2 years after the investigation of T cell subsets, there was no increased mortality for recipients of EZ vaccine. Hence it is unlikely that high titer vaccine has an persistent adverse effect on survival after 3 years of age.

 

Sex-specific differences in mortality after high-titre measles immunization in rural Senegal.

Aaby,-P; Samb,-B; Simondon,-F; Knudsen,-K; Seck,-A-M; Bennett,-J; Markowitz,-L; Rhodes,-P; Whittle,-H

Bull-World-Health-Organ. 1994; 72(5): 761-70

Bulletin-of-the-World-Health-Organization

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.

 

Sex differences in the humoral antibody response to live measles vaccine in young adults.

Green,-M-S; Shohat,-T; Lerman,-Y; Cohen,-D; Slepon,-R; Duvdevani,-P; Varsano,-N; Dagan,-R; Mendelson,-E

Int-J-Epidemiol. 1994 Oct; 23(5): 1078-81

International-journal-of-epidemiology

BACKGROUND. Following vaccination of children using high-titre live measles vaccine, excess non-specific mortality was reported, particularly among females. Since vaccination with live measles virus results in a temporary depression of the immune response to other antigens, the female predominance in subsequent non-measles mortality may be due to sex differences in response to live measles vaccines. METHODS. In this study, the immunogenicity of standard titre live Schwarz strain measles vaccine was examined 2 and 4 weeks post-vaccination in 223 males and 66 female aged 18-20 years in Israel in 1991. RESULTS. Females had higher post-vaccination geometric mean titre (GMT) at all levels of pre-vaccination titres at both 2 and 4 weeks. Furthermore, after controlling for differences in pre-vaccination titres, overall the post-vaccination GMT for females was about 50% higher than for males (P < 0.001). CONCLUSIONS: These findings indicate that females exhibit a stronger humoral immune response to measles vaccine. Possible sex differences in immunosuppression following measles vaccination should be explored.

 

Long-term survival after Edmonston-Zagreb measles vaccination in Guinea-Bissau: increased female mortality rate.

Aaby,-P; Knudsen,-K; Whittle,-H; Lisse,-I-M; Thaarup,-J; Poulsen,-A; Sodemann,-M; Jakobsen,-M; Brink,-L; Gansted,-U; et-al.

J-Pediatr. 1993 Jun; 122(6): 904-8

Journal-of-pediatrics,-The

In an urban area of Guinea-Bissau, 384 children were enrolled in a randomized trial comparing morbidity and mortality rates after receiving high-titer Edmonston-Zagreb (EZ) measles vaccine administered from 4 months of age, with a control group receiving inactivated poliomyelitis vaccine at 4 months of age and the standard Schwarz vaccine from 9 months of age. Children were followed to the age of at least 3 years. The mortality ratio of the EZ vaccinees compared with control subjects was 1.79 (range, 1.06 to 3.02; p = 0.027) if children were excluded at the time of migration; if deaths after migration were included, the mortality ratio was 1.53 (range, 0.94 to 2.49; p = 0.087). Girls in the EZ group had significantly higher mortality rates than girls in the control group (mortality ratio = 1.95; range, 1.07 to 3.56; p = 0.027); there was no difference for the boys (mortality ratio = 0.98; range, 0.41 to 2.30). Adjustment for background factors in a Cox regression model did not modify these estimates. Furthermore, female recipients of EZ vaccine had more days with diarrhea (relative risk = 1.35; range, 1.17 to 1.56; p = 0.00003) and were more likely than control subjects to visit a health center in the month after vaccination (relative risk = 1.86; range, 1.05 to 3.31; p = 0.027); those who consulted were more likely to die subsequently (mortality ratio = 2.31; range, 0.99 to 5.41; p = 0.054). These observations were unplanned and require confirmation in larger studies.

 

Differential mortality by measles vaccine titer and sex.

Holt,-E-A; Moulton,-L-H; Siberry,-G-K; Halsey,-N-A

J-Infect-Dis. 1993 Nov; 168(5): 1087-96

Journal-of-infectious-diseases,-The

Mortality was evaluated in 1972 children who had received measles vaccines at 6-11 months of age that were 10-fold (medium titer) or 100-fold (high titer) greater than standard titer. Mortality among boys did not differ by vaccine titer and was similar to mortality in children who received standard-titer vaccine. Girl recipients of high-titer vaccine had somewhat greater mortality than girls who received medium-titer vaccine (risk ratio = 1.71, 95% confidence interval = 0.91-3.24). Increased mortality was associated with high-titer vaccine for girls but not for boys (P = .04). There was no evidence of selection bias or preferential health care by sex that might explain the differential mortality. This mortality pattern has been noted in two other populations with high background infant and childhood mortality. The biologic basis for this effect on mortality has not been determined. Data from this and other studies have resulted in discontinuation of the use of high-titer measles vaccines.

 

Divergent mortality for male and female recipients of low-titer and high-titer measles vaccines in rural Senegal.

Aaby,-P; Samb,-B; Simondon,-F; Knudsen,-K; Seck,-A-M; Bennett,-J; Whittle,-H

Am-J-Epidemiol. 1993 Nov 1; 138(9): 746-55

American-journal-of-epidemiology

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.