Francis E. André

Hepatitis B epidemiology in Asia, the Middle East and Africa

Asia and Africa have previously been classified as areas of high endemicity for hepatitis B virus (HBV), but in some countries highly effective vaccination programmes have shifted this pattern towards intermediate or low endemicity. Thus, China is now the only country in Asia where HBV endemicity is high. Countries with intermediate endemicity include India, Korea, the Philippines, Taiwan and Thailand, and those with low endemicity include Japan, Pakistan, Bangladesh, Singapore, Sri Lanka and Malaysia. Most countries in Africa have high HBV endemicity, with the exceptions of Tunisia and Morocco, which have intermediate endemicity. Zambia has borderline intermediate/high endemicity. In the Middle East, Bahrain, Iran, Israel and Kuwait are areas of low endemicity, Cyprus, Iraq and the United Arab Emirates have intermediate endemicity, and Egypt, Jordan, Oman, Palestine, Yemen and Saudi Arabia have high endemicity. All of these Middle East countries reach a large proportion of their population with hepatitis B vaccination, which is reducing the infection rate, particularly in Saudi Arabia. The vaccination programme in Taiwan has also greatly reduced the HBV infection rate. Future vaccination programmes must take into account the mode of transmission of HBV, the healthcare infrastructure to deliver vaccination, and the socioeconomic and political factors in each individual country, to determine the most cost-effective way of infection control.

Clinical efficacy of the RIT 4237 live attenuated bovine rotavirus vaccine in infants vaccinated before a rotavirus epidemic.

In a randomized, double-blind, placebo-controlled trial, 331 infants aged 6 to 12 months received orally, at an interval of 1 month, either two doses of live attenuated bovine rotavirus vaccine strain RIT 4237 or equivalent placebo. The vaccinations were carried out during September to November, a non-rotavirus season; only three cases of rotavirus diarrhea occurred in the study group before the vaccinations were completed. During the epidemic season from December to May, 31 patients with clinically significant rotavirus diarrhea required therapy. Five of these were among the 168 vaccine recipients, and 26 among the 160 placebo recipients (P less than 0.001), giving a vaccine protection rate of 82%. The incidence of clinically significant diarrhea from all causes was reduced by 76% in the vaccinees. As determined by an enzyme immunoassay antibody test with homologous virus antigen, seroconversion after vaccination was obtained in 53% of the initially seronegative infants. Clinical protection correlated well with seroconversion, but the vaccinees who failed to seroconvert also had less rotavirus diarrhea than the placebo recipients, suggesting that immunity may be mediated by factors other than serum EIA antibody. Seventeen of the 23 rotavirus isolates in the epidemic season that were typed were of serotype 1, two were of serotype 2, and four were of serotype 3. The protection rates against clinically significant diarrhea were 72%, 100%, and 100% for serotypes 1, 2, and 3, respectively. We conclude that epidemic infantile winter diarrhea associated with human rotaviruses can be significantly reduced by vaccination with the live attenuated RIT 4237 bovine rotavirus vaccine before the epidemic season.

IMMUNOGENICITY AND SAFETY OF LIVE ORAL ATTENUATED BOVINE ROTAVIRUS VACCINE STRAIN RIT 4237 IN ADULTS AND YOUNG CHILDREN

A candidate oral live rotavirus vaccine, strain RIT 4237, of bovine origin, was tested for immunogenicity and safety in man. In adults the vaccine did not cause clinical symptoms, and a booster response in rotavirus serum antibodies was seen in 2/20 subjects. In seronegative young children one oral dose induced seroconversion to homologous virus in 15/17 (88%) children seronegative by enzyme immunoassay and in 13/19 (68%) children seronegative by a neutralisation assay. The vaccine did not produce gastrointestinal or constitutional symptoms in the children, nor did it cause rotavirus excretion in the stools. The results suggest that the RIT 4237 strain is a promising candidate for a vaccine against human rotavirus, and the vaccine-induced immunity against natural human rotavirus infection should be evaluated in future trials.

Clinical assessment of the safety and efficacy of an inactivated hepatitis A vaccine: rationale and summary of findings

The objectives for the clinical testing of the inactivated hepatitis A vaccine developed by SmithKline Beecham Biologicals are reviewed and the results obtained are summarized. The first studies were carried out in healthy young adult volunteers using pilot vaccine lots prepared from the CLF and HM175 strains of hepatitis A virus (HAV). It was established that the candidate vaccines were well-tolerated, caused no hypersensitivity reactions and elicited a strong antibody response. As the yield in production with the HM175 strain was higher it was preferred over the CLF strain for further development of a vaccine. A dose-range study with HM175 vaccine in adults showed that an antigen dose of 720 ELISA units (El.U) produced almost 100% seroconversion after one injection. This dose was therefore chosen as appropriate for adults. A dose of 360 El.U was used in children. To date, a total of 67 studies in 18 countries involving 47,145 subjects, including 20,586 control subjects, have been initiated. In these studies, 55,259 doses of HM175-derived hepatitis A vaccine have so far been administered. This extensive experience has shown that the vaccine is well-tolerated, causing essentially only mild, transient local reactions. Vaccine reactogenicity was assessed using symptom checklists, filled in by the volunteers or their parents, for a period of 4 days following vaccination. Blood samples were obtained at different times after vaccination to evaluate the immune response. Clinical studies with six different lots, manufactured using commercial-scale production methods, have been carried out on 2901 adults. These studies have shown that a seroconversion rate of 95.7% (1225/1280) is obtained one month after the first vaccine dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Persistence of vaccine-induced antibody to hepatitis A virus

A level of 10 mIU hepatitis A antibodies/ml as measured by ELISA is believed to be the minimal protective concentration. If this level is considered, the mean persistence of vaccine induced antibodies is approximately 10-11 years after booster dose, 6-7 years if only the primary doses are given and 5-6 years if the minimal individual titre is taken into account.

Evaluation of RIT 4237 Bovine Rotavirus Vaccine in Newborn Infants: Correlation of Vaccine Efficacy to Season of Birth in Relation to Rotavirus Epidemic Period

A single oral dose of bovine rotavirus vaccine RIT 4237 or placebo was given to 2 groups of 5-day-old infants, born in October 1984 (n = 244) and June 1985 (n = 245), who remained in follow-up for 2.8 and 2.0 years, respectively. The vaccine had no effect on the total number of detectable episodes of rotavirus diarrhoea: there were 22 cases in the vaccinees and 24 in the placebo recipients in the October group and 18 and 16 respectively in the June group. However, vaccination decreased significantly the clinical severity of rotavirus diarrhoea, as assessed by a numerical score 0-20; this vaccine effect was much greater in the infants born in October. The mean severity scores for vaccine and placebo recipients were 4.55 and 10.75 respectively in the October group (p less than 0.0001, t-test) and 8.2 and 11.6 respectively in the June group (p = 0.010, t-test). Vaccine-induced clinical protection against rotavirus diarrhoea did not correlate well with serological response after vaccination, but showed good correlation to the presence of rotavirus antibodies before the rotavirus epidemic season. It is concluded that bovine rotavirus vaccine is more efficacious when given immediately before the rotavirus epidemic season: the vaccine effect may be amplified by exposure to wild rotaviruses during the season.

Efficacy of two doses of RIT 4237 bovine rotavirus vaccine for prevention of rotavirus diarrhoea

ABSTRACT. Vesikari T., Ruuska T., Delem A., André F. E., Beards G. M. and Flewett T. H. (Department of Clinical Sciences, University of Tampere, Tampere, Finland, and the Biological Division, Smith Kline RIT Rixensart, Belgium and WHO Collaborating Centre for Reference and Research on Human Rotaviruses, East Birmingham Hospital, Birmingham, U.K.). Efficacy of two doses of RIT 4237 bovine rotavirus vaccine for prevention of rotavirus diarrhoea. Acta Paediatr Scand 80: 173, 1991.

Dose-response study of RIT 4237 oral rotavirus vaccine in breast-fed and formula-fed infants.

The RIT 4237 live attenuated bovine rotavirus vaccine was given orally at three dose levels to 75 breast-fed, 40 formula-fed and 24 fasting infants ages 4 to 6 months. Vaccine of 10(8.3) (50% tissue culture-infective doses) (TCID50) per dose gave a neutralizing antibody response in 14 of 14 (100%) formula-fed, in 18 of 26 (69%) breast-fed and in 5 of 8 (63%) fasting infants, or an overall response rate of 77% (37 of 48). The overall response rate to a vaccine of 10(7.2) TCID50 per dose was 61% (33 of 49), or slightly but not significantly lower than that at the higher dose level. On the other hand a vaccine of 10(6.3) TCID50 per dose gave a significantly (P less than 0.01) lower composite response rate of 33% (14 of 42). The overall serologic response rate to the vaccine at the two higher doses was somewhat better (24 of 28, 86%) in formula-fed infants than in breast-fed infants (37 of 52, 71%). However, the response rate of the breast-fed infants can also be considered satisfactory. Thus the current recommendation for use of the RIT 4237 vaccine would be administration of a dose of at least 10(8) TCID50 after feeding with either formula or breast milk.

Oral Rotavirus Vaccination in Breast- and Bottle-Fed Infants Aged 6 to 12 Months

ABSTRACT. Oral bovine rotavirus vaccine RIT 4237 was tested at two dose levels in 217 children between 6 and 12 months of age who received either breast milk or bottle milk (cows milk or infant formula) before vaccination. Of the children 65% were initially seronegative for rotavirus ELISA IgG and IgM antibody. The full vaccine dose (108,3 50% tissue culture infective doses, TCID50) induced seroconversion rates 81% and 86% and booster response rates 69% and 64% in breast and bottle‐fed children, respectively. There was no difference in the vaccine response of infants receiving cows milk or infant formula either. It is concluded that the RIT 4237 rotavirus vaccine at the dose level 108,3 TCID50, gives a satisfactory response in both breast‐ and bottle‐fed children in this age group, but multiple vaccinations may be needed for maximal efficacy.

Effect of virus strain and antigen dose on immunogenicity and reactogenicity of an inactivated hepatitis A vaccine

A randomized double-blind comparison of five killed hepatitis A vaccine preparations was carried out with eligible medical student and staff volunteers. Vaccines were prepared in M RC-5 cells and formalin-inactivated. Three monthly injections of 1 ml in the deltoid muscle were given. Group A received the CLF strain at a dose of 360 ELISA units (El.U) in 0.5 mg aluminium hydroxide (n = 35). The other groups received the HM175 strain as follows: 180 El.U in 1 mg aluminium hydroxide (to group B, n = 42), 360 El.U in 0.5 mg aluminium hydroxide (to group C, n = 40), 360 El.U in 1 mg aluminium hydroxide (to group D, n = 39) and 720 El.U in 1 mg aluminium hydroxide (to group E, n = 43). The geometric mean anti-HAV concentration (GMC) measured in mIV/ml by an ELISA method one month after each injection were: group A, 223, 480, 1635; group B, 123, 221, 649; group C, 185, 365, 1085; group D, 144, 323, 1076; group E, 229, 646, 2521. At month 6, the GMC had fallen by approximately 20%. Seroconversion as measured by ELISA was 100% in groups A and E after one injection, and 100% in all groups after three injections; after two injections, only one subject in group C was still negative. The dose effect with HM175 vaccine was significant. There was a good correlation between ELISA and neutralization (radioimmunofocus inhibition test) titres. One month after the second dose, all subjects in groups A and E had both hepatitis A virus immunoglobulin M (HAV IgM) geometric mean titre, (GMT > 5000) and IgG (GMT > 25,000) as measured by a sensitive terminal dilution ELISA.(ABSTRACT TRUNCATED AT 250 WORDS)