Acute encephalopathy followed by permanent brain injury or death associated with further attenuated measles vaccines: a review of claims submitted to the National Vaccine Injury Compensation Program.

OBJECTIVE: To determine if there is evidence for a causal relationship between acute encephalopathy followed by permanent brain injury or death associated with the administration of further attenuated measles vaccines (Attenuvax or Lirugen, Hoechst Marion Roussel, Kansas City, MO), mumps vaccine (Mumpsvax, Merck and Co, Inc, West Point, PA), or rubella vaccines (Meruvax or Meruvax II, Merck and Co, Inc, West Point, PA), combined measles and rubella vaccine (M-R-Vax or M-R-Vax II, Merck and Co, Inc, West Point, PA), or combined measles, mumps, and rubella vaccine (M-M-R or M-M-R II, Merck and Co, Inc, West Point, PA), the lead author reviewed claims submitted to the National Vaccine Injury Compensation Program. METHODS: The medical records of children who met the inclusion criteria of receiving the first dose of these vaccines between 1970 and 1993 and who developed such an encephalopathy with no determined cause within 15 days were identified and analyzed. RESULTS: A total of 48 children, ages 10 to 49 months, met the inclusion criteria after receiving measles vaccine, alone or in combination. Eight children died, and the remainder had mental regression and retardation, chronic seizures, motor and sensory deficits, and movement disorders. The onset of neurologic signs or symptoms occurred with a nonrandom, statistically significant distribution of cases on days 8 and 9. No cases were identified after the administration of monovalent mumps or rubella vaccine. CONCLUSIONS: This clustering suggests that a causal relationship between measles vaccine and encephalopathy may exist as a rare complication of measles immunization.

Chronic arthropathy and musculoskeletal symptoms associated with rubella vaccines. A review of 124 claims submitted to the National Vaccine Injury Compensation Program.

OBJECTIVE: To report the outcome of 124 claims of chronic arthropathy associated with rubella vaccine submitted to the National Vaccine Injury Compensation Program. METHODS: Medical records and testimony were reviewed separately by physicians and Special Masters to determine the clinical diagnosis and eligibility for compensation under the Program. RESULTS: Among the 124 subjects with chronic arthropathy, the onset occurred between 1 week and 6 weeks after the rubella vaccination in 72, and < 1 week or > 6 weeks after the vaccination in 52. Various conditions developed in the 2 onset groups (1-6 weeks postvaccination, < 1 week or > 6 weeks postvaccination), including, respectively, unspecified arthritis (n = 29, n = 1), specified arthritis (n = 11, n = 19), arthralgia (n = 24, n = 7), fibromyalgia (n = 4, n = 11), and multiple symptoms with minimal arthralgia or myalgia (n = 4, n = 14). Concordance of medical recommendations by Program physicians and Special Masters' decisions in 56 completed claims was 91%, with awards mainly to patients with chronic unspecified arthritis and arthralgia. CONCLUSION: The Program and the US Court of Federal Claims have accepted a causal relationship between currently used rubella vaccine in the US and some chronic arthropathy with an onset between 1 week and 6 weeks after vaccine administration.

Reporting vaccine-associated paralytic poliomyelitis: concordance between the CDC and the National Vaccine Injury Compensation Program.

This paper compares cases of paralytic poliomyelitis reported to the systems operated by the National Vaccine Injury Compensation Program and the Centers for Disease Control and Prevention (CDC) for reporting of adverse events associated with vaccination. Of the 118 cases of vaccine-associated paralytic poliomyelitis determined by either system, 18 were reported initially only to the compensation program, 50 only to the CDC, and 50 to both. The annual incidence of vaccine-associated paralytic poliomyelitis determined from data from both systems varied from 6 to 13 cases (mean = 9.1) a year, with an increase of 1.4 cases a year when initial reports only to the compensation program are included. Thus, the compensation program provides important supplemental incidence data.

Completeness of reporting for paralytic poliomyelitis, United States, 1980 through 1991. Implications for estimating the risk of vaccine-associated disease.

BACKGROUND: Although the risk of vaccine-associated paralytic poliomyelitis (VAPP) has remained relatively constant during the past 30 years, estimates of VAPP depend largely on the completeness of reporting to the existing passive surveillance system. The National Vaccine Injury Compensation Program constitutes an alternative system for reporting VAPP, and data available from this system permitted us to evaluate the completeness of the national poliomyelitis surveillance system. METHODS: We compared cases of paralytic poliomyelitis reported to the national surveillance system (maintained by the Centers for Disease Control and Prevention, Atlanta, Ga) with cases recommended for compensation by the National Vaccine Injury Compensation Program, Rockville, Md, and we calculated the observed completeness of reporting to the national system for 1980 through 1991. A capture-recapture method was also used to estimate completeness of reporting, ie, to account for cases potentially missed by both systems. In addition, we reviewed the epidemiology and updated the risk of VAPP based on the most current information on cases of VAPP. RESULTS: From 1980 through 1991, 105 cases of paralytic poliomyelitis were identified by the Centers for Disease Control and Prevention and National Vaccine Injury Compensation Program systems, 98 (93%) of which were VAPP (average, 8.2 cases per year). The observed completeness of reporting to the Centers for Disease Control and Prevention was 94%, and the estimated completeness of reporting (capture-recapture method) was 81%. The overall risk of VAPP was one case per 2.5 million doses of oral poliovirus vaccine distributed. In the sensitivity analysis, the risk estimates of VAPP remained relatively stable throughout a wide range of assumptions regarding underreporting and specificity of the case definition for paralytic poliomyelitis. CONCLUSION: The risk of VAPP remains virtually unchanged from previous estimates despite the inclusion of previously unidentified VAPP cases. Despite the potential for both underreporting and misclassification of cases, our risk estimates were relatively insensitive to either of these biases. Since both of these biases were in opposite directions, and both probably occurred with low frequency, the risk estimates provided in this report appear valid and approximate the "true" risk of VAPP in the United States.

Oka/Merck varicella vaccine in healthy children: final report of a 2-year efficacy study and 7-year follow-up studies.

A large double-blind, randomized, placebo-controlled trial of live attenuated Oka/Merck varicella vaccine was conducted among healthy children, 1-14 years of age. During the first varicella season, the efficacy of the vaccine among susceptible children was 100%1. During the second varicella season, 22 children were diagnosed with varicella; 21 cases in placebo recipients and one in a vaccine recipient. The overall efficacy of the vaccine through two varicella seasons was 98%. After the code for the study was broken, the original group of vaccine recipients continued to be followed for development of varicella. The estimated proportion of vaccine recipients who remained varicella-free at the end of 7 years was 95%. The 23 cases of varicella that occurred in vaccine recipients over the 7-year period were considerably milder than natural varicella. The average number of lesions was 53, 50% of the children had non-vesicular rashes, and 14% of the children had a temperature greater than or equal to 38.9 degrees C (102 degrees F), oral. The persistence of antibody in a subset of vaccine recipients followed for 6 years was 100%.

Protective effects of Towne cytomegalovirus vaccine against low-passage cytomegalovirus administered as a challenge.

To test the protective effect of Towne live attenuated human cytomegalovirus (HCMV) vaccine in normal individuals, we developed a parenteral challenge consisting of a low-passage isolate (Toledo stain) inoculated subcutaneously in graded doses. This challenge virus caused a mild mononucleosis syndrome in seronegative individuals at doses of 10 or 100 pfu. The illness was accompanied by atypical lymphocytosis, raised hepatic enzymes, excretion of HCMV and HCMV-specific immune responses. Naturally seropositive volunteers also developed clinical and laboratory evidence of infection after challenge with 1,000 pfu of Toledo but resisted 10 or 100 pfu. Volunteers who had been vaccinated 1 y earlier also were resistant to disease caused by 10 or 100 pfu of Toledo, although some were asymptomatically infected by the 100 pfu dose. Vaccine-induced immunity to HCMV was as complete as naturally induced immunity when the challenge dose of Toledo was 10 pfu.

Live Oka/Merck varicella vaccine in healthy children. Further clinical and laboratory assessment.

A clinical trial among 137 healthy children, ages 1 to 12 years, was conducted with four different doses (4,350, 870, 435, and 43 plaque-forming units [pfu]) of live Oka/Merck varicella vaccine to evaluate clinical reactions and selected laboratory parameters and to determine the minimum effective dose and induction time of antibody. The vaccine was well tolerated with no significant difference in the rate of reported symptoms by dose. The frequency of varicellalike rash was 3% (4/137); all rashes were mild. Serum aminotransferase values were essentially unchanged after vaccination. Minor variations found in platelet counts after vaccination were not associated with any bleeding, bruising, or clotting. Among initially seronegative children who received doses of 435 pfu or greater, 94% assayed at two weeks and 100% assayed at four or six weeks seroconverted. The geometric mean titers were similar for all four doses at six weeks. IgG and IgA responses were demonstrated with no relation to the vaccine dose.

Live attenuated varicella virus vaccine. Efficacy trial in healthy children.

We conducted a double-blind, placebo-controlled efficacy trial of the live attenuated Oka/Merck varicella vaccine among 956 children between the ages of 1 and 14 years, with a negative clinical history of varicella. Of the 914 children who were serologically confirmed to be susceptible to varicella, 468 received vaccine and 446 received placebo. The vaccine produced few clinical reactions and was well tolerated. There was no clinical evidence of viral spread from vaccinated children to sibling controls. Approximately eight weeks after vaccination, 94 per cent of the initially seronegative children who received vaccine had detectable antibody to varicella. During the nine-month surveillance period, 39 clinically diagnosed cases of varicella, 38 of which were confirmed by laboratory tests, occurred among study participants. All 39 cases occurred in placebo recipients; no child who received vaccine contracted varicella. The vaccine was 100 per cent efficacious in preventing varicella in this population of healthy children (P less than 10(-9).

Vaccine against human hepatitis B virus prepared from antigen derived from human hepatoma cells in culture.

Vaccine against human hepatitis B was prepared using antigen derived from hepatitis B carrier hepatoma cells grown in the interstices of a Diaflo hollow filter unit. Hepatitis B surface antigen (HBsAg) produced by these cells was purified by immune affinity chromatography, digestion with DNase and pepsin, and Sephadex G-150 separation. The Formalin-treated antigen was formulated in 20-micrograms dose on alum adjuvant with thimerosal added as a preservative. This cell culture vaccine was as potent as human plasma-derived vaccine as measured in a mouse potency assay. The vaccine proved safe in tests in chimpanzees and in human subjects who were in late stages of cancer of the central nervous system and who were receiving therapy for their condition. None of five subjects who received the vaccine developed untoward clinical reactions. Two of the subjects who received all three doses of vaccine developed antibody against HBsAg. Three persons, two given only the primary doses and one who was given all three doses but was lost to follow-up, demonstrated no response. The slow and relatively low antibody responses to the vaccine were similar to those in other immunosuppressed persons who were given vaccine of human plasma origin.

Live attenuated varicella vaccine: the KMcC strain in healthy children.

The KMcC strain of live, attenuated varicella-zoster virus vaccine was studied in healthy children as a preliminary step toward varicella vaccine studies with this strain in children with leukemia. Forty-three children were immunized: 26 with the 40th passage vaccine and 17 with the 50th passage. Studies included surveillance for clinical reactivity, oropharyngeal excretion of vaccine virus, viruria, and viremia. Antibody responses were assayed by fluorescent antibody to membrane antigens and immune adherence hemagglutination. Cell-mediated immune responses were assayed by lymphocyte proliferation to varicella-zoster virus specific antigens. There was 100% seroconversion to the KMcC passage 40 and 50 vaccines (by fluorescent antibody to membrane antigen assay). Every child studied developed in vitro lymphocyte proliferation to varicella-zoster virus antigens. Papular skin lesions, probably vaccine related, occurred in 31% of the 40th passage vaccinees but in only 6% of the 50th passage vaccinees. The 50th passage KMcC strain vaccine is sufficiently immunogenic and safe to initiate clinical studies with leukemia patients.

Live attenuated varicella vaccine: immunization of healthy children with the OKA strain.

Ninety-one healthy children were immunized with one of three preparations of the OKA strain of live attenuated varicella zoster virus in order to gain sufficient information on safety and immunogenicity to justify vaccine studies in immunosuppressed children. The OKA-Biken vaccine was studied in a dose response trial. Two additional clinical trails were conducted with the OKA strain that was further passaged: a frozen aqueous (OKA-RIT-Aq) form and a lyophilized (OKA-RIT-Ly) form were tested. With each of these vaccines clinical reactivity was minimal and virus shedding, viremia, and transmission of the vaccine virus were absent. Excellent seroconversion rates of 100 and 94% were induced with approximately 500 pfu of OKA-Biken and OKA-RIT-Ly vaccine, respectively. A lower seroconversion rate was noted for OKA-RIT-Aq, presumably on the basis of defective individual vials. Diluted OKA-Biken vaccine induced less seroconversion but even the 5 pfu dose produced antibody responses in 81% of the vaccinees. In vitro specific cellular immune responses to varicella virus antigens were demonstrated in each group of vaccinees, including all but two of those vaccines who failed to seroconvert. The data indicate that two preparations of the OKA strain are sufficiently safe and immunogenic in healthy children to support further studies in immunocompromised children.

Streptococcus pneumoniae polysaccharide vaccine: age and dose responses, safety, persistence of antibody, revaccination, and simultaneous administration of pneumococcal and influenza vaccines.

Contemporary 14-valent pneumococcal polysaccharide vaccine was first licensed in 1977 in the United States, where about four million doses of vaccine have been distributed to date. The vaccine induces excellent antibody responses in elderly persons as well as in young adults. The antigen content of the vaccine is 50 microgram of each serotype of polysaccharide per dose, and lower titers of antibody are induced when the dose is reduced to 25 or 12.5 microgram of antigen. Adverse reactions are usually mild and consist principally of local erythema and induration at the injection site, with mild fever in a small proportion of subjects. Antibody persists well for at least four years, and it is expected that immunity will last for at least 5 years after vaccination. Local and systemic reactions to the vaccine may be greater when a second dose of vaccine is administered within three years after the initial dose, and this reactivity appears to be due to a Arthus-like response that results from local formation of antigen-antibody complexes. Pneumococcal and influenza vaccines can be injected simultaneously into separate sites without impairment of antibody responses to either vaccine; this feature should facilitate administration of these two vaccines.