RESEARCH VACCINE TURNED DEADLY TO THIRD WORLD BABIES -----W. Cooley-Prost worth@igc.apc.org FACT SHEET *1987 Major studies of high dose EZ measles vaccine started in Haiti, Senegal, Mexico,1 Guinea Bissau. EZ vaccine in normal doses had been used in Europe since 1970s and by UNICEF since 1988, but high dose EZ was made specifically for studies in the Third World. Researchers hoped that very high doses -- 10 to 500 times normal -- would overwhelm the maternal antibodies that normally prevent a young infant's immune system from responding to measles vaccine. *October 1989 WHO recommended high dose EZ for 6-month-old babies in Third World countries, changing a long-standing policy of delaying measles vaccine until at least 9 months. In the U.S., the usual age for measles vaccine is 15 months. CDC announced a contract with Kaiser for the Los Angeles study, and filed an Investigational New Drug application with FDA. *April 1990 The director of an African study site alerted WHO and CDC to possible mortality increase in babies given high dose EZ. Mortality data from the Senegal and Guinea Bissau sites were borderline then, but by that fall were statistically significant. Still, the problem was reportedly ignored, dismissed or contradicted by CDC and WHO researchers for many months. *June 1990 Los Angeles trial began enrolling inner-city minority infants as young as 6 months. Funded by CDC and NIH, about 1,500 black and Hispanic babies were enrolled. *February 1991 The mortality data were deemed inconclusive at a vaccine committee meeting, and studies continued. The investigator who identified the mortality problem decided the only ethical alternative was to publish his findings whether the other researchers agreed or not. *April-May 1991 Haiti study mortality data was collected by Johns Hopkins researchers, but according to subsequent independent analysis, they located only 63% of the high dose EZ babies. *October 1991 Lancet published the African mortality data. WHO's vaccine committee asked all study sites to submit their mortality data for independent analysis, and scheduled a June 1992 meeting to address the results. Enrollment was halted in Los Angeles, and followup studies began there in 1992. *June 1992 Independent analysis confirmed increased mortality in high dose EZ babies, especially girls. The mortality pattern suggested lasting immunosuppression. Analysis conducted by the London School of Hygiene and Tropical Health found "consistent evidence of increased mortality risk..." *August 1993 NIH's Office of Protection from Research Risks visited CDC during an investigation of the Los Angeles study and a complaint about failure to inform parents of the vaccine's experimental status, risk of adverse reactions, and possible long term problems. *June 1996 CDC director Satcher explained that Los Angeles parents weren't informed of EZ vaccine's experimental status because of "a little mistake." (Los Angeles Times, June 17, 1996) 1 The Mexico study enrolled about 1,400 babies, but excluded those with malnutrition, any immune disorder, a history of measles or measles vaccination, or recent oral polio vaccine. Thus, this population was not comparable to either the other study populations or usual Third World populations. Mortality followup was done in spring 1992, but no data on infants in the Mexico or Los Angeles studies were submitted for WHO's independent analysis. The CDC measles expert who led both studies, currently in Thailand overseeing a project related to AIDS vaccine, did write the independent analyst that mortality was not increased in either study. worth@igc.apc.org FACT SHEET: SELECTED REFERENCES Note: Fact Sheet information is drawn from a wide range of sources, including: published medical literature, mainstream press, and materials from WHO, CDC, FDA, NIH, PAHO and other agencies; government project and funding databases; documents obtained under the Freedom of Information Act; regulatory, clinical and bioethics documents; unpublished reports; correspondence; and numerous interviews between 1994 and 1996 in seven states and three foreign countries. Persons interviewed include principal investigators and other research workers involved in the EZ studies; other physicians, research professionals and study site personnel; U.S. government officials, senior compliance officers, attorneys and agency staff; foreign government officials, including Ministers of Health, Social Affairs and Foreign Affairs; university faculty members; vaccine experts; journalists; and nonprofit organization staff. Citations selected from over 150 references are provided below. 1987 Major studies of high dose EZ measles vaccine... * Haiti-- Job JS, Halsey NA, et al. Successful immunization of infants at 6 months of age with high dose Edmonston-Zagreb measles vaccine. Pediatr Infect Dis J 1991; 10(4):303-311. * Senegal-- Garenne M, Leroy O, et al. Efficacy, safety and immunogenicity of two high-titre measles vaccines: Final Report, ORSTOM, Dakar, June 1991. Also Garenne M, Leroy O, et al. High-titer measles virus vaccines: protection evaluation. In Measles and Poliomyelitis, ed. by E. Kurstak, Springer-Verlag 1993: 119-131. * Mexico-- Markowitz LE, Sepulveda J, et al. Immunization of six- month-old infants with different doses of Edmonston-Zagreb and Schwarz measles vaccines. N Eng J Med 1990; 322:580-587. * Guinea Bissua-- Aaby P, Jensen TG, et al. Trial of high-dose Edmonston-Zagreb measles vaccine in Guinea-Bissau: protective efficacy. Lancet 1988; i:809-811, and 811-814 (antibody response and side effects). * Standard titer EZ vaccine: Ikic D, Jazbasic M, et al. Attenuation and characterization of Edmonston-Zagreb measles virus. Ann Immunol Hung 1972; 16:175-181. October 1989 WHO recommended high dose EZ... Expanded Programme on Immunisation. Safety and efficacy of high titre measles vaccine at 6 months of age. Weekly Epidemiol Rec 1990; 65:5-12. * Los Angeles study: Kaiser/CDC contract #200-89-0736 (9-30-89). * Office of Protection from Research Risks, National Institutes of Health. Evaluation of human subject protections in research conducted by the Centers for Disease Control and the Agency for Toxic Substances and Disease Registry, Sept. 25, 1995. January & April 1990 The directors of two African study sites alerted WHO... Garenne M, Leroy O, et al. Child mortality after high-titre measles vaccines: prospective study in Senegal. Lancet, Oct. 12, 1991; 338:903-907, 920. * Fine P, xxxxxxxxxxxx * Also interviews 1/95 - 7/96 (Arlington VA, Boston, Geneva, Paris). June 1990 Los Angeles trial began enrolling... CDC press materials, June 1996. Office of Protection from Research Risks, National Institutes of Health. Evaluation of human subject protections in research conducted by the Centers for Disease Control and the Agency for Toxic Substances and Disease Registry, Sept. 25, 1995. February 1991 The mortality data were deemed inconclusive... Expanded Programme on Immunisation. Safety and efficacy of high titre measles vaccine at 6 months of age. Weekly Epidemiol Rec 1991; 66:249-251, and 1992; 67:357-360. * Also interviews 1/95 - 4/96 (Arlington VA, Boston, Paris, Washington DC). worth@igc.apc.org April-May 1991 Haiti study mortality data collected... Holt EA, Moulton LH, et al. Differential mortality by measles vaccine titer and sex. J Infect Dis 1993; 168:1087-1096. Also Dowell SF, Davis HL, et al. The utility of verbal autopsies for identifying HIV-1-related deaths in Haitian children. AIDS 1993; 7:1255-1259. Also London School of Hygiene & Tropical Medicine, mortality analysis presented in Atlanta GA, June 1992. October 1991 Lancet published... Garenne M, Leroy O, et al. Child mortality after high-titre measles vaccines: prospective study in Senegal. Lancet, Oct. 12, 1991; 338:903-907, 920. Aaby P, et al. Child mortality after high-titre measles vaccine in the Senegal: the complete data set. Lancet 1991; 338:1518 and Garenne M, et al, 1519. June 1992 Independent analysis confirmed... London School of Hygiene & Tropical Medicine, mortality analysis presented in Atlanta GA, June 1992. * High-titre measles vaccine dropped. Lancet, July 25, 1992; 340:232. * Haiti-- Holt EA, Moulton LH, et al. Differential mortality by measles vaccine titer and sex. J Infect Dis 1993; 168(5): 1087-1096. * Halsey NA. Increased mortality after high titer measles vaccine: too much of a good thing. Pediatr Infect Dis J 1993; 12-462- 465. August 1993 NIH's OPRR visited CDC... Office of Protection from Research Risks, National Institutes of Health. Evaluation of human subject protections in research conducted by the Centers for Disease Control and the Agency for Toxic Substances and Disease Registry, Sept. 25, 1995. June 1996 CDC director Satcher explained... Cimons M. CDC says it erred in measles study; Agency failed to tell parents that one of two vaccines used on infants in L.A. during epidemic was experimental, officials say. Los Angeles Times, June 17, 1996. Also CDC and Kaiser press materials, June-August 1996. cities / states: Arlington VA (Michel, Barbara), Vienna VA (NVIC 1995, 1996) Atlanta GA (Rosenthal, CDC) Baltimore MD (Halsey et al), Bethesda (OPRR, OAR, NIH); Rockville (FDA, FOI offices) Boston MA (Maria Madison) Los Angeles CA (Michael Marcy) Miami FL (Kathi Maternowska) New York NY (Michelle Karshan, Ron Howell) Washington DC (Maurice Hilleman, USAID, PAHO) cities / countries: Geneva, Suisse (Clements) Paris, France (Michel) Port-au-Prince, Haiti (Boulos, many others)
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