Theodore F. Tsai

New initiatives for the control of Japanese encephalitis by vaccination: minutes of a WHO/CVI meeting, Bangkok, Thailand, 13-15 October 1998.

Japanese encephalitis (JE) is a leading cause of viral encephalitis in Asia that, in several countries, has been controlled effectively through national vaccine programs. However, in recent years, transmission has been recognized or has intensified in new locations where the available vaccines are either unaffordable or unlicensed. In addition, the near-eradication of poliomyelitis from Asia has elevated JE in the public health agenda of preventable childhood diseases, and surveillance of acute neurological infections to confirm polio eradication, simultaneously, has led to a greater awareness of the disease burden attributable to JE. The only internationally licensed JE vaccine, an inactivated mouse-brain derived vaccine, is efficacious but is problematic from the perspectives of reactogenicity, requirement for numerous doses, cost and reliance on a neurological tissue substrate. A live-attenuated vaccine distributed only in China also is efficacious and requires fewer doses; however, production and regulatory standards are unresolved. Several approaches toward developing novel JE vaccines that could fill the gap in JE vaccine need are under pursuit. The minutes and recommendations of a meeting of experts to discuss these issues, jointly sponsored by the World Health Organization and the Childrens Vaccine Initiative in Bangkok, Thailand, 13-15 October, 1998, are presented.

Epidemic Yersinia enterocolitica Infection Due to Contaminated Chocolate Milk

In September and October, 1976, an outbreak of illness due to chocolate milk contaminated with Yersinia enterocolitica resulted in hospitalization of 36 children, 16 of whom had appendectomies. Infection with Y. enterocolitica serotype 0:8 was demonstrated in 38 ill persons. Sixty-one per cent of the persons who were infected had a titer greater than 1:160 OH agglutinins to serotype 8 yersinia, whereas 48 per cent of the hospitalized children had a fourfold change in agglutinin titer. An epidemiologic investigation demonstrated that illness was associated with drinking of chocolate milk purchased in school cafeterias, and Y. enterocolitica 0:8 was subsequently isolated from the milk. The investigation suggested that the bacterium was introduced at the dairy during the mixing by hand of chocolate syrup with previously pasteurized milk.

Fever and multisystem organ failure associated with 17D-204 yellow fever vaccination: a report of four cases

BACKGROUNDnIn 1998, the US Centers for Disease Control and Prevention was notified of three patients who developed severe illnesses days after yellow fever vaccination. A similar case occurred in 1996. All four patients were more than 63 years old.nnnMETHODSnVaccine strains of yellow fever virus, isolated from the plasma of two patients and the cerebrospinal fluid of one, were characterised by genomic sequencing. Clinical samples were subjected to neutralisation assays, and an immunohistochemical analysis was done on one sample of liver obtained at biopsy.nnnFINDINGSnThe clinical presentations were characterised by fever, myalgia, headache, and confusion, followed by severe multisystemic illnesses. Three patients died. Vaccine-related variants of yellow fever virus were found in plasma and cerebrospinal fluid of one vaccinee. The convalescent serum samples of two vaccinees showed antibody responses of at least 1:10240. Immunohistochemical assay of liver tissue showed yellow fever antigen in the Kuppfer cells of the liver sample.nnnINTERPRETATIONnThe clinical features, their temporal association with vaccination, recovery of vaccine-related virus, antibody responses, and immunohistochemical assay collectively suggest a possible causal relation between the illnesses and yellow fever vaccination. Yellow fever remains an important cause of illness and death in South America and Africa; hence, vaccination should be maintained until the frequency of these events is quantified.

Oil-in-Water Emulsion Adjuvant with Influenza Vaccine in Young Children

BACKGROUNDnThe efficacy of inactivated influenza vaccines is known to be poor in infants and young children.nnnMETHODSnWe studied the effect of the adjuvant MF59, an oil-in-water emulsion, on the efficacy of trivalent inactivated influenza vaccine (TIV) in 4707 healthy children 6 to less than 72 months of age who had not previously been vaccinated against influenza. The children were randomly assigned to three study groups, each of which received the assigned vaccines in two doses, 28 days apart, during two consecutive influenza seasons. Two of the groups were given age-appropriate doses of TIV either with or without the MF59 adjuvant, and the third group was given control (noninfluenza) vaccines to assess their absolute and relative efficacy against influenza-like illness, as confirmed by means of polymerase-chain-reaction (PCR) assay.nnnRESULTSnAttack rates of influenza-like illness across both influenza seasons were 0.7%, 2.8%, and 4.7% in the adjuvant, nonadjuvant, and control vaccine groups, respectively. The absolute vaccine efficacy rates against all influenza strains (94 of 110 cases were due to vaccine-matched H3N2 viruses) were 86% (95% confidence interval [CI], 74 to 93) for the MF59-adjuvant vaccine (ATIV) and 43% (95% CI, 15 to 61) for the vaccine without the adjuvant (TIV); the relative vaccine efficacy rate for ATIV versus TIV was 75% (95% CI, 55 to 87). The efficacy rates for ATIV were 79% (95% CI, 55 to 90) in children 6 to less than 36 months of age and 92% (95% CI, 77 to 97) in those 36 to less than 72 months of age, as compared with 40% (95% CI, -6 to 66) and 45% (95% CI, 6 to 68), respectively, for TIV. Antibody responses were higher with ATIV and remained so through day 181. The rates of systemic and local reactions to the influenza vaccines with and without the adjuvant were similar in the younger age group (relative risk, 1.04; 95% CI, 0.98 to 1.09), but systemic events in the older age group were more frequent after administration of ATIV (63%) than after administration of TIV (44%) or the control vaccine (50%). Serious adverse events were distributed evenly across the three vaccine groups.nnnCONCLUSIONSnInfluenza vaccine with the MF59 adjuvant is efficacious against PCR-confirmed influenza in infants and young children. (Funded by Novartis Vaccines and Diagnostics; ClinicalTrials.gov number, NCT00644059.).

La Crosse Encephalitis in Children

BACKGROUNDnLa Crosse encephalitis is a mosquito-borne disease that can be mistaken for herpes simplex encephalitis. It has been reported in 28 states but may be underrecognized.nnnMETHODSnWe investigated the manifestations and clinical course of La Crosse encephalitis in 127 patients hospitalized from 1987 through 1996. The diagnosis was established by serologic testing for IgM and IgG antibodies to La Crosse virus. Data were collected by chart review.nnnRESULTSnMost of the patients were school-aged children (mean [+/-SD] age, 7.8+/-3.5 years; range, 0.5 to 15.0). Symptoms included headache, fever, and vomiting (each in 70 percent or more of the patients), seizures (in 46 percent), and disorientation (in 42 percent). Thirteen percent had aseptic meningitis. Hyponatremia developed in 21 percent, and there were signs of increased intracranial pressure in 13 percent. Six patients, including three with cerebral herniation, underwent intracranial-pressure monitoring. The 13 patients (11 percent) whose condition deteriorated in the hospital had decreases in serum sodium levels (P=0.007), and increases in body temperature (P=0.003) at the time of deterioration. At admission, these patients more often had a history of vomiting (P=0.047) and a score of 12 or lower on the Glasgow Coma Scale (P=0.02) than the others; a trend toward a greater prevalence of seizures at admission was also evident in this group (P=0.07). All the patients survived, but 15 of them (12 percent) had neurologic deficits at discharge. Follow-up assessments, performed in 28 children, suggested an increase in cognitive and behavioral deficits 10 to 18 months after the episode of encephalitis.nnnCONCLUSIONSnLa Crosse virus infection should be considered in children who present with aseptic meningitis or encephalitis. Hyponatremia and increasing body temperature may be related to clinical deterioration.

Anaphylaxis from yellow fever vaccine

BACKGROUNDnThere are very few reports of anaphylactic reactions to yellow fever (YF) vaccine in the literature, and these date from the 1940s.nnnOBJECTIVEnWe sought to estimate the rate of YF vaccine-related anaphylaxis.nnnMETHODSnAll reports of adverse reactions to YF vaccine submitted to the Vaccine Adverse Event Reporting System between 1990 and 1997 were reviewed for those meeting criteria for probable or possible anaphylactic reactions.nnnRESULTSnOf 243 reports submitted, 40 describe probable or possible anaphylactic reactions. In 22 of these 40, YF vaccine was the only vaccine administered. There were 5,236,820 doses of YF vaccine distributed in the United States during this period. By using all 40 cases, the rate of YF vaccine-related anaphylaxis would be 40 in 5, 236,820 or about 1 in 131,000. In 35 of the reports, information was provided on whether previous doses of YF vaccine had been given. In 34 of these 35, the reaction occurred after the first dose of YF vaccine, suggesting that vaccine constituents other than the viral proteins may have been the allergens. The vaccine is grown in chicken embryos and contains gelatin as a stabilizer.nnnCONCLUSIONnYF vaccine can cause anaphylactic reactions. Persons presenting for YF vaccine should be asked if they have had adverse reactions to previous doses of this or other vaccines and if they are allergic to eggs, chicken, or gelatin. Health care workers administering YF vaccine should be prepared to recognize and treat anaphylactic reactions should they occur.

Adverse events after Japanese encephalitis vaccination: review of post-marketing surveillance data from Japan and the United States.

We determined the reporting rates for adverse events following the administration of inactivated mouse-brain derived Japanese encephalitis vaccine (JEV) based on post-marketing surveillance data from Japan and the United States. The rate of total adverse events per 100,000 doses was 2.8 in Japan and 15.0 in the United States. In Japan, 17 neurological disorders were reported from April 1996 to October 1998 for a rate of 0.2 per 100,000 doses. In the United States, no serious neurological adverse events temporally associated with JEV were reported from January 1993 to June 1999. Rates for systemic hypersensitivity reactions were 0.8 and 6.3 per 100,000 doses in Japan and the United States, respectively. Passively collected VAERS surveillance data indicate that characteristic hypersensitivity reactions with a delayed onset continue to occur among JEV recipients and that conservative recommendations limiting its use to travelers at high risk of infection with Japanese encephalitis are appropriate.

Short-Term Safety of Live Attenuated Japanese Encephalitis Vaccine (SA14-14-2): Results of a Randomized Trial with 26,239 Subjects

The short-term safety of an effective and inexpensive new live attenuated Japanese encephalitis vaccine (SA14-14-2) was studied in a randomized trial, using block randomization. Of 26,239 children who were enrolled, half received the vaccine and half served as controls. Subjects were prospectively followed for 30 days for severe adverse events, such as encephalitis, meningitis, and all-cause hospitalization. No cases of encephalitis or meningitis occurred in either group. The upper 95% confidence limit for adverse events not occurring among subjects receiving their first dose was 4.1/10,000. Risk ratios and 95% confidence intervals for other adverse events were 0.70 (0.43-1.15) for all-cause hospitalization, 0.91 (0.37-2.22) for seizure, and 0.79 (0.56-1.11) for fever lasting > or = 3 days. These data attest to the short-term safety of the SA14-14-2 virus strain and the hamster kidney cell substrate.

Continued Transmission of West Nile Virus to Humans in Southeastern Romania, 1997–1998

After an epidemic of West Nile (WN) virus neurologic infections in southeastern Romania in 1996, human and animal surveillance were established to monitor continued transmission of the virus. During 1997 and 1998, neurologic infections were diagnosed serologically as WN encephalitis in 12 of 322 patients in 19 southeastern districts and in 1 of 75 Bucharest patients. In addition, amid a countrywide epidemic of measles, the etiology of the febrile exanthem in 2 of 180 investigated cases was determined serologically to be WN fever; 1 case was complicated by hepatitis. Sentinel chickens placed in Bucharest seroconverted to WN virus during the summer months, indicating their potential value in monitoring transmission. The continued occurrence of sporadic WN infections in southeastern Romania in consecutive years after the 1996 epidemic is consistent with local enzootic transmission of the virus.

CALIFORNIA–LA CROSSE ENCEPHALITIS

La Crosse encephalitis, a mosquito-borne viral disease that can be mistaken for herpes simplex encephalitis, is under-recognized in the United States, despite case reports from 28 states and an incidence in endemic areas (20-30/100,000) exceeding that of bacterial meningitis. The disease recurs every summer in endemic foci in the midwestern and mid-Atlantic United States in areas forested with hardwood trees, which provide breeding sites for the treehole-dwelling mosquito vector, Aedes triseriatus. La Crosse encephalitis should be considered in the child presenting with meningoencephalitis in summer and early fall, particularly for children living in (or recent travel to) endemic areas in mid-Atlantic and midwestern states.