High dose Edmonston Zagreb (EZ) measles vaccine

High dose Edmonston Zagreb (EZ) measles vaccine

[Book 1996] Outrage! How babies were used as guinea pigs in a LA county vaccine experiment. The Conscious Rasta Report Vol3, Issue 6, Aug 1996-Keidi Obi Awadu

Edmonston-Zagreb and Schwarz standard-titre measles vaccine

Garenne M, Leroy O, Beau JP, Sene I.Child mortality after high-titre measles vaccines: prospective study in Senegal. Lancet. 1991 Oct 12;338(8772):903-7. PMID: 1681265
The use of Edmonston-Zagreb high-titre (EZ-HT) vaccine at age 6 months has been recommended for countries in which measles before the age of 9 months is a substantial cause of death, but little is known about the long-term effects of high-titre live measles vaccines given early in life. In a randomised vaccine trial in a rural area of Senegal, children were randomly assigned at birth to three vaccine groups: EZ-HT at 5 months (n = 336); Schwarz high-titre (SW-HT) at 5 months (n = 321); and placebo at 5 months followed by standard low-titre Schwarz vaccine at 10 months (standard: n = 358). All children were prospectively followed for 24-39 months in a well-established demographic surveillance system. Child mortality after immunisation was significantly higher in the two groups which received high-titre vaccines than in the group given the standard vaccine. The relative risk of death was 1.80 (95% confidence interval [CI] 1.18-2.74; p = 0.007) in the EZ-HT group and 1.51 (0.97-2.34; p = 0.07) in the SW-HT group compared with the standard group. The three vaccine groups were comparable as regards various social, family, and health characteristics, and there was no difference in mortality between children who received the standard vaccine and those who were eligible for the trial but did not take part for various reasons. The higher risk of death in the two high-titre vaccine groups remained significant in multivariate analyses. These findings suggest a need to reconsider the use of high-titre measles vaccines early in life in less developed countries.

Seng R, Samb B, Simondon F, Cisse B, Soumare M, Jensen H, Bennett J, Whittle H, Aaby P. Increased long term mortality associated with rash after early measles vaccination in rural Senegal. Pediatr Infect Dis J. 1999 Jan;18(1):48-52. PMID: 9951980 [PubMed - indexed for MEDLINE]

OBJECTIVES: To examine whether clinical symptoms, including rash, were more common after measles immunization compared with placebo and to study the association between postvaccination symptoms and later mortality. DESIGN: Examination of side effects in the 3 weeks after immunization in a trial of high titer and standard titer measles vaccines. PATIENTS: Two hundred twenty-four children randomly selected to be included in the surveillance for diarrhea, fever and rash. RESULTS: There was no difference in fever and diarrhea between recipients of high titer vaccines and recipients of placebo. However, high titer recipients tended to have more measles-like rashes than placebo recipients [relative risk, 2.12 (range, 0.90 to 5.03)]. Among recipients of high titer vaccines, children who presented a rash had higher mortality in the following 5 to 7 years than those who did not develop rash [mortality rate ratio, 3.85 (range, 1.52 to 9.79)]. High titer recipients without a rash had the same mortality as children in the placebo group who were given standard doses of measles vaccine at 10 months of age [mortality rate, 0.76 (range, 0.35 to 1.62)]. CONCLUSIONS: These observations suggest that in this particular study, rash after high titer measles vaccine may identify children who received a particularly high dose of vaccine or children with more severe and persistent postvaccination immunosuppression. Whether high titer vaccine is more likely than standard titer measles vaccine to provoke such reaction is not known, given that we did not compare side effects after different titers of measles vaccine. Future trials of live measles vaccine should monitor the development of rash.

Hall AJ, Cutts FT. Lessons from measles vaccination in developing countries. BMJ. 1993 Nov 20;307(6915):1294-5. No abstract available. PMID: 8257878 [PubMed - indexed for MEDLINE]

Aaby P, Samb B, Simondon F, Knudsen K, Seck AM, Bennett J, Markowitz L, Whittle H.A comparison of vaccine efficacy and mortality during routine use of high-titre Edmonston-Zagreb and Schwarz standard measles vaccines in rural Senegal.Trans R Soc Trop Med Hyg. 1996 May-Jun;90(3):326-30.PMID: 8758096

Vaccine efficacy and mortality in successive cohorts of children who routinely received either Edmonston-Zagreb high-titre (EZ-HT) or Schwarz standard (SW-STD) measles vaccines have been examined in a rural area of Senegal. The 2 vaccines were equally protective against measles infection (vaccination efficacy: EZ-HT 94%; SW-STD 93%). Children who did not attend a scheduled session to receive measles vaccine had a higher mortality rate between 9 months and 2 years of age than did children receiving either EZ-HT (mortality ratio [MR] = 1.81, 95% confidence interval [CI] 1.06-3.08) or SW-STD measles vaccine (MR = 1.74, 95% CI 0.95-3.21). Children of either sex vaccinated with EZ-HT had lower mortality than their equivalents who had not received any measles vaccine. There was no difference in overall mortality between recipients of EZ-HT and SW-STD (MR = 0.96, 95% CI 0.70-1.30). Using a Cox regression analysis to adjust for sex, age and significant background factors (season and death of mother), mortality rates tended to be lower for male recipients of EZ-HT than for boys receiving SW-STD (MR = 0.73, 95% CI 0.50-1.11) and higher for girls receiving EZ-HT than for girls receiving SW-STD (MR = 1.30, 95% CI 0.81-2.09) (test of interaction between sex and vaccine, P = 0.067). The tendency to reduced survival benefit for girls following receipt of high-titre measles vaccines substantiated observations from randomized trials in Guinea-Bissau, Senegal and Haiti. Existing data provide little support for the notion that high-titre vaccine is deleterious but it may not have the same beneficial effects as standard-titre measles vaccine.

Aaby P, Samb B, Simondon F, Knudsen K, Seck AM, Bennett J, Markowitz L, Whittle H. Five year follow-up of morbidity and mortality among recipients of high-titre measles vaccines in Senegal. Vaccine. 1996 Feb;14(3):226-9. PMID: 8920704
At 3-5 years of age, female recipients of Edmonston-Zagreb high-titre (EZ-HT) and Schwarz high-titre (SW-HT) measles vaccine had lower survival rates than female recipients of Schwarz standard measles vaccine (SW-STD) in Guinea-Bissau, Senegal and Haiti. In Senegal, the children who received high-titre vaccines have now been followed to the age of 5-7 years to determine whether the difference in mortality persisted, and whether differences in vaccine efficacy were apparent. At this age there was no difference in mortality between female recipients of high-titre and standard titre measles vaccines. There was no indication that high-titre EZ-HT vaccine at 5 months (EZ-HT,5m) provided suboptimal protection, as vaccine efficacy after exposure was 97% and 95%, respectively, for EZ-HT,5m and SW-STD,10m vaccines, whereas SW-HT,5m vaccine had an efficacy of 81%. The difference in mortality between recipients of high-titre vaccines and SW-STD observed in several studies during the first few years after vaccination may be explained by non-specific beneficial effects of the standard measles vaccine rather than a harmful effect of the high-titre vaccines.

Aaby P, Lisse IM, Whittle H, Knudsen K, Thaarup J, Poulsen A, Sodemann M, Jakobsen M, Brink L, Gansted U, et al. Long-term survival in trial of medium-titre Edmonston-Zagreb measles vaccine in Guinea-Bissau: five-year follow-up. Epidemiol Infect. 1994 Apr;112(2):413-20. PMID: 8150016

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.

Aaby P, Knudsen K, Whittle H, Lisse IM, Thaarup J, Poulsen A, Sodemann M, Jakobsen M, Brink L, Gansted U, et al. Long-term survival after Edmonston-Zagreb measles vaccination in Guinea-Bissau: increased female mortality rate. J Pediatr. 1993 Jun;122(6):904-8. PMID: 8501567

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.

Whittle H, Hanlon P, O'Neill K, Hanlon L, Marsh V, Jupp E, Aaby P. Trial of high-dose Edmonston-Zagreb measles vaccine in the Gambia: antibody response and side-effects. Lancet. 1988 Oct 8;2(8615):811-4. PMID: 2902264 [PubMed - indexed for MEDLINE]

In a randomised trial, infants living in a large village in The Gambia were immunised either at 4 months of age with 40,000 plaque forming units (PFU) of the Edmonston-Zagreb (EZ) measles vaccine or at the usual age of 9 months with 6000 TCID50 of a conventional Schwarz measles vaccine. Measles developed in 2 of 119 children who received the EZ vaccine, in 1 before and in the other after 9 months of age. In the Schwarz group measles developed in 7 of 120 children--in 5 before and in 2 after 9 months of age. Serological responses measured at 5 months after vaccination and at 18 months of age were satisfactory in both groups although in the Schwarz group levels were on average 2-fold higher than in the EZ group. The frequencies of fever, cough, vomiting, and diarrhoea were no higher in the EZ vaccinees in the 3 weeks following vaccination than in age-matched non-immunised controls. Long-term morbidity as assessed by clinic attendances and weight at 18 months of age was much the same in the two groups. The EZ measles vaccine is thus safe and clinically and serologically effective when used in a high dose to immunise young Gambian infants.

Aaby P, Jensen TG, Hansen HL, Kristiansen H, Tharup J, Poulsen A, Sodemann M, Jakobsen M, Knudsen K, Clotilde da Silva M, et al. Trial of high-dose Edmonston-Zagreb measles vaccine in Guinea-Bissau: protective efficacy. Lancet. 1988 Oct 8;2(8615):809-11. PMID: 2902263
In a randomised study of 558 children in an urban African community, the protective effect of the Edmonston-Zagreb (EZ) measles vaccine given in a dose of 40,000 plaque forming units from the age of 4 months was compared with the effects of a standard dose (6000 tissue culture infectious units) of Schwarz measles vaccine given from the age of 9 months. During two years of follow-up, all 14 clinical cases of measles occurred in the Schwarz group; 10 of the children contracted measles before vaccination and 4 after measles vaccination. Thus the EZ vaccine provided significant protection against measles both before and after the usual age of vaccination. Among the children who were exposed to measles at home, those given EZ vaccine were better protected than either unvaccinated children or those given the Schwarz vaccine.
Aaby P, Samb B, Simondon F, Knudsen K, Seck AM, Bennett J, Whittle H. Divergent mortality for male and female recipients of low-titer and high-titer measles vaccines in rural Senegal. Am J Epidemiol. 1993 Nov 1;138(9):746-55.PMID: 8237989 [PubMed - indexed for MEDLINE]
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.

Samb B, Aaby P, Whittle H, Seck AM, Simondon F.Protective efficacy of high-titre measles vaccines administered from the age of five months: a community study in rural Senegal. Trans R Soc Trop Med Hyg. 1993 Nov-Dec;87(6):697-701. PMID: 8296384 [PubMed - indexed for MEDLINE]

Using data on incidence and secondary attack rates, we examined the protective efficacy of high-titre Edmonston-Zagreb (EZ) and Schwarz (SW-HT) measles vaccines administered at 5 months. Control children were assigned to placebo at age 5 months and standard Schwarz (SW-std) measles vaccine at 9-10 months of age. A large proportion of measles cases was verified serologically. Though high-titre vaccines seemed to be protective before 10 months of age, a significant reduction in disease could not be demonstrated due to low incidence of measles. After 10 months of age, SW-std given at 10 months gave a vaccine efficacy of 100% and induced better protection than SW-HT (P = 0.030) and EZ-HT (P = 0.128) administered at 5 months. In studies of secondary attack rates in the compound, vaccine efficacy was 91% (75%-97%) for EZ-HT, 85% (40%-96%) for SW-HT, and 100% for SW-std. Attack rates were correlated with intensity of exposure (P = 0.0006), being much higher for children exposed in the same hut than for those living in the same compound but in a different household (relative risk = 3.36 [1.32-8.57]). The attack rate was significantly lower among vaccinated than unvaccinated children with no detectable measles antibody (relative risk = 0.41 [0.18-0.93]). In rural areas with a high coverage in the surrounding community, a single dose at 9-10 months may provide sufficient protection. Since high-titre vaccines have been associated with higher mortality than SW-std, further improvements in measles control before 9 months may require two-dose strategies with standard vaccines.

Lisse IM, Aaby P, Knudsen K, Whittle H, Andersen H. Long term impact of high titer Edmonston-Zagreb measles vaccine on T lymphocyte subsets. Pediatr Infect Dis J. 1994 Feb;13(2):109-12. PMID: 8190534 [PubMed - indexed for MEDLINE]

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.

Edmonston-Zagreb and Schwarz standard-titre measles vaccine

Garly ML, Bale C, Martins CL, Monteiro M, George E, Kidd M, Dias F, Aaby P, Whittle HC. Measles antibody responses after early two dose trials in Guinea-Bissau with Edmonston-Zagreb and Schwarz standard-titre measles vaccine: better antibody increase from booster dose of the Edmonston-Zagreb vaccine. Vaccine. 2001 Feb 28;19(15-16):1951-9. PMID: 11228365 [PubMed - indexed for MEDLINE]

In Guinea-Bissau, children were randomised at 6 months of age to receive either two doses of standard-titre measles vaccine at 6 and 9 months of age or an inactivated polio vaccine at 6 months and standard-titre measles vaccine at 9 months of age. During the first 5 months, children received Edmonston-Zagreb (EZ) vaccine and during the following 11 months, the Schwarz (SW) vaccine. Five percent of the mothers, 74% of children at 6 months of age, and 92% of unvaccinated children at 9 months of age had unprotective levels (<125 mIU/ml) of measles antibodies. Among children receiving EZ vaccine, 1% were unprotected at 18 months of age after either two (3/240) or one (3/211) doses of vaccine, the geometric mean measles antibody titre (GMT) being approximately 1550 mIU/ml in both groups. Among those receiving SW vaccine 9% (34/365) and 3% (9/310) were unprotected at 18 months of age in the two-dose and the one-dose groups (RR = 3.21 (95% confidence interval (CI) 1.56-6.58)), respectively. The GMT was higher after one dose of SW vaccine at 9 months of age (2491 mIU/ml) than after two doses of SW vaccine (1125 mIU) (P < 0.001). In the EZ vaccine group, there was no significant difference in antibody level for children vaccinated in the presence of high or low levels of maternal antibodies, whereas there was a marked difference in the SW group. The second EZ vaccine induced a significant antibody increase between 9 months of age (1191 mIU) and 18 months of age (1602 mIU, P=0.011), whereas antibody levels tended to decline from 9 months (1243 mIU) to 18 months of age (998 mIU, P = 0.124) after the second dose of SW vaccine. Conclusively, after two doses of EZ measles vaccine more children were protected at 18 months of age than after two doses of SW. One dose of SW provided the highest antibody response, but a higher proportion of unprotected than one or two doses of EZ. The EZ vaccine was less sensitive to maternal antibodies, and able to increase the antibody response by revaccination, while the second SW vaccine resulted in an unchanged or lower antibody response.

Hussey GD, Goddard EA, Hughes J, Ryon JJ, Kerran M, Carelse E, Strebel PM, Markowitz LE, Moodie J, Barron P, Latief Z, Sayed R, Beatty D, Griffin DE. The effect of Edmonston-Zagreb and Schwarz measles vaccines on immune response in infants. J Infect Dis. 1996 Jun;173(6):1320-6. PMID: 8648203 [PubMed - indexed for MEDLINE]
The effects of measles immunization on immune responses in infants and the roles of vaccine strain and age of immunization are not known. Eighty-eight children were immunized at 6 or 9 months of age with the Edmonston-Zagreb (EZ) or Schwarz (SW6, SW9) strain of measles vaccine. Children were studied before and 2 weeks and 3 months after immunization. Seroconversion was similar, but geometric mean neutralizing titers at 3 months differed by vaccine group: SW9, 1367 mIU/mL; SW6, 982; and EZ, 303 (P = .003). Mitogen-induced lymphoproliferation was decreased at 2 weeks in the SW9 group and at 3 months in all groups and was negatively correlated with measles antibody level at 3 months (r = -.387, P = .003). CD8 T cells, soluble CD8, neopterin, and beta2-microglobulin were increased at 2 weeks in the SW9 group, and soluble CD8 and beta2-microglobulin remained elevated at 3 months. Therefore, measles immunization resulted in suppression of lymphoproliferation, which was most evident in infants with the highest antibody responses and most immune activation.