Comparative studies of measles vaccines in a controlled trial in the USSR

This paper describes the results of a study of measles vaccines carried out in the USSR on 866 children aged 12-54 months as part of a WHO-sponsored collaborative programme of investigation on live and killed measles vaccines. The live vaccines studied were Beckenham 20, Enders Edmonston B, Milovanović, Schwarz and Smorodincev. Of these, Beckenham 20 caused the most reaction (as assessed by pyrexia and rash) and Milovanović the least. Antibody responses were highest for Beckenham 20 and Schwarz vaccines and for Enders Edmonston vaccine plus gamma-globulin. A study was also made of the effect of one inoculation of Pfizer (killed) vaccine followed by one of Enders Edmonston B or Smorodincev live vaccine; very few reactions were observed in children vaccinated in this way and the antibody response was good.     

A controlled field trial and laboratory study of five typhoid vaccines in the USSR

A controlled field trial of typhoid vaccines was carried out in the USSR in 1962. It was the fifth and last of a series. Five preparations were tested, the most effective being a heat-killed divalent vaccine prepared from aerated broth culture. The results of a laboratory study of the vaccines were not in complete agreement with the data from the field trial. No correlation was found between the effectiveness of vaccines and the data from laboratory tests as to their potency, and the authors suggest that differences in effectiveness may be due to varying degrees of damage to biological components during the different production processes. The effectiveness is also sensitive to dosage.     

A controlled field trial of the effectiveness of cholera and cholera El Tor vaccines in the Philippines

A controlled field trial on some 584 000 people in an endemic cholera El Tor area in the Philippines demonstrated that cholera vaccines gave moderate protection of short duration. Injection of a single dose of vaccine prepared from either Vibrio cholerae or El Tor vibrios gave over 50% protection for the first 2 months. The immunity conferred by the V. cholerae vaccine declined rapidly after 3 to 4 months. The effectiveness of the El Tor vaccine continued for 6 months. An oil-adjuvant vaccine prepared from V. cholerae conferred an equally high degree of protection for a longer period of time, but, owing to severe vaccination reactions, its use could not be recommended.     

A controlled field trial of the effectiveness of cholera and cholera El Tor vaccines in the Philippines: Preliminary report

In a controlled field trial on some 584 000 people in an endemic cholera El Tor area in the Philippines, it was demonstrated that cholera vaccines gave moderate protection of short duration. Injection of a single dose of vaccine prepared from either Vibrio cholerae or Vibrio El Tor gave over 50% protection for the first two months. The immunity conferred by the V. cholerae vaccine rapidly declined after three to four months. The V. El Tor vaccine gave protection for six months, but its effectiveness declined. An oil-adjuvant vaccine prepared from V. cholerae conferred an increasing degree of protection of long duration, but, owing to severe vaccination reactions, its use could not be recommended.     

Results of the study of typhoid vaccines in four controlled field trials in the USSR

In field trials of typhoid vaccine in the USSR, a comparison was made of the effectiveness of chemical, heat-killed, and alcoholized vaccines. All of them conferred protection if administered in sufficient dosage, and variations in effectiveness could usually be traced to size of dosage. The heat-killed vaccine, however, appeared to be significantly more effective than the others. The immunological history of a vaccinated person apparently had no essential influence on the effectiveness of a vaccine, and the data indicated that two doses of the vaccine conferred no greater protection than one.     

Controlled field trial of the effectiveness of cholera and cholera El Tor vaccines in Calcutta

To assess the effectiveness of cholera vaccines, 2 controlled field trials were made in Calcutta—an endemic area—during 1964 and 1965. Three Indian vaccines of which 1 was grown on casein hydrolysate and 2 on agar, a freeze-dried vaccine from the Walter Reed Army Institute of Research (WRAIR), Washington, D.C., and an El Tor vaccine from the Philippines were used, with typhoid-paratyphoid (TAB) vaccine as a control. The 210 112 volunteers were vaccinated subcutaneously with a single dose of one of the vaccines.     

A controlled field trial of the effectiveness of monovalent classical and El Tor cholera vaccines in the Philippines

Monovalent Ogawa and Inaba vaccines prepared from classical and El Tor strains of Vibrio cholerae were field-tested in Negros Occidental, Philippines, where cholera El Tor, serotype Ogawa, is endemic. The monovalent classical Ogawa and Inaba vaccines were of the same lots as those tested in East Pakistan in 1968-69. The results indicated that all four types of vaccine tested offered significant degrees of protection varying from 58% to 71%. The Ogawa vaccines were slightly, though not significantly, more protective than the Inaba vaccines against disease caused by Ogawa. The biotypes of the vaccine strains were found to be of no consequence.     

Nonparticipation as a determinant of adverse health outcomes in a field trial of oral cholera vaccines.

The authors estimated the incidence rates of cholera and death between 1985 and 1988 for 32,642 age- and sex-eligible persons who did not participate in a randomized, placebo-controlled field trial of killed oral cholera vaccines in rural Bangladesh. As compared with 20,744 placebo recipients, the relative risk of cholera for all nonparticipants, adjusted for potentially confounding demographic variables, was 1.20 (95% confidence interval (CI) 1.03-1.41); this adjusted relative risk reflected elevated adjusted relative risks in nonparticipants who were medically ineligible (RR = 1.65; 95% CI 1.22-2.22) or refused to participate (RR = 1.19; 95% CI 1.01-1.41), but not in persons absent at the time of vaccination (RR = 1.00; 95% CI 0.78-1.28). The adjusted relative risk of death was also elevated in nonparticipants as compared with placebo recipients (RR = 1.28; 95% CI 1.10-1.48), with the same pattern of adjusted relative risks for different categories of nonparticipants: for ineligible subjects, 2.64 (95% CI 2.12-3.29); for refusers, 1.20 (95% CI 1.02-1.41); and for absentees, 0.95 (95% CI 0.75-1.22). The authors concluded that nonparticipation was associated with clinically cogent adverse health outcomes, but that the magnitude of these associations varied according to the reason for nonparticipation. These findings underscore the caution required in assessing vaccine efficacy with controls who are not vaccinated because of choices made by patients or vaccinators.     

A controlled field trial of plain and aluminium hydroxide-adsorbed cholera vaccines in Surabaya, Indonesia, during 1973--75.

A controlled field trial comparing the effectiveness of a plain cholera vaccine with that of a vaccine adsorbed to aluminium hydroxide was carried out in a cholera-endemic area of Indonesia during 1973-75. Tetanus toxoid adsorbed to aluminium phosphate was used as the control. In vaccinees aged 1-4 years, the adsorbed cholera vaccine provided about 88% protection for 6 months following vaccination and still provided about 50% protection between 11 and 14 months after vaccination. In the same age group, the plain vaccine provided only 53% protection during the first 6 months and no appreciable protection beyond that period. In those aged 5 years and over, both vaccines provided 50-60% protection throughout the period of observation (14 months). Neither vaccine caused any serious side effects.     

Field trial of oral cholera vaccines in Bangladesh: evaluation of anti-bacterial and anti-toxic breast-milk immunity in response to ingestion of the vaccines

In a field trial conducted in Bangladesh, ingestion of either B subunit-killed whole cell (BS-WC) or killed whole cell (WC) oral cholera vaccines by mothers was associated with a 47% reduction of the risk of cholera in their non-vaccinated children aged under 36 months. Because vaccine-induced breast-milk immunity seemed a possible explanation for these findings, we evaluated anti-lipopolysaccharide (LPS) and anti-cholera toxin (CT) IgA antibody responses in breast milk collected during the trial from 53 lactating women who ingested three doses of BS-WC, WC, or an Escherichia coli K12 strain (K12). Despite induction of moderate vibriocidal (1.4 to 2.0-fold) and anti-CT (4.5-fold) serum antibody responses, the vaccines did not elicit significant rises of anti-LPS or anti-CT IgA breast-milk antibodies. The failure of the vaccines to elicit significant levels of breast-milk anti-cholera antibodies suggests an alternative explanation for protection of young children by maternal vaccination, such as interruption of maternal-child transmission of Vibrio cholerae 01.     

A controlled field trial of an aluminium phosphate-adsorbed cholera vaccine in Calcutta

A controlled field trial to determine the efficacy of a single dose of an aluminium phosphate-adsorbed cholera vaccine was conducted in Calcutta during 1975-77. An aluminium phosphate-adsorbed tetanus toxoid was used as the placebo. Follow-up of the immunized volunteers for a period of two years showed that the adsorbed cholera vaccine provided 100% protection to children under five years of age for 6 months, 88.9% for 12 months, and 91.7% for 18 months (P<0.05). The overall protection for all age groups was 58.5% for 18 months. There were no serious side effects following the anti-cholera inoculations.     

Laboratory tests of typhoid vaccines used in a controlled field study

In 1954-55, a controlled field trial of two types of typhoid vaccine—alcoholized (“vaccine A”) and phenolized (“vaccine F”)—prepared in Yugoslavia was carried out in the town and district of Osijek. In an attempt to correlate the protection conferred on man by these vaccines with their potency in laboratory animals, arrangements were made for laboratory tests to be performed jointly by the Central Institute of Hygiene, Zagreb, Yugoslavia; the Lister Institute of Preventive Medicine, Elstree, Herts, England; and the Walter Reed Army Institute of Research (WRAIR), Washington, D.C., USA. In this paper, the results of the WRAIR tests are presented.     

Randomised field trial to evaluate serological response after foot-and-mouth disease vaccination in Turkey

Despite years of biannual mass vaccination of cattle, foot-and-mouth disease (FMD) remains uncontrolled in Anatolian Turkey. To evaluate protection after mass vaccination we measured post-vaccination antibodies in a cohort of cattle (serotypes O, A and Asia-1). To obtain results reflecting typical field protection, participants were randomly sampled from across Central and Western Turkey after routine vaccination. Giving two-doses one month apart is recommended when cattle are first vaccinated against FMD. However, due to cost and logistics, this is not routinely performed in Turkey, and elsewhere. Nested within the cohort, we conducted a randomised trial comparing post-vaccination antibodies after a single-dose versus a two-dose primary vaccination course.Four to five months after vaccination, only a third of single-vaccinated cattle had antibody levels above a threshold associated with protection. A third never reached this threshold, even at peak response one month after vaccination. It was not until animals had received three vaccine doses in their lifetime, vaccinating every six months, that most (64% to 86% depending on serotype) maintained antibody levels above this threshold. By this time cattle would be >20 months old with almost half the population below this age. Consequently, many vaccinated animals will be unprotected for much of the year. Compared to a single-dose, a primary vaccination course of two-doses greatly improved the level and duration of immunity. We concluded that the FMD vaccination programme in Anatolian Turkey did not produce the high levels of immunity required. Higher potency vaccines are now used throughout Turkey, with a two-dose primary course in certain areas.Monitoring post-vaccination serology is an important component of evaluation for FMD vaccination programmes. However, consideration must be given to which antigens are present in the test, the vaccine and the field virus. Differences between these antigens affect the relationship between antibody titre and protection.     

Preparation and laboratory testing of plain and aluminum hydroxide-adsorbed cholera vaccines used in a field trial in Indonesia.

Two types of cholera vaccine were prepared: a plain vaccine and an aluminium hydroxide-adsorbed vaccine, by using the Inaba NIH 35A3 and Ogawa NIH 41 serotypes of Vibrio cholerae. For cultivation, a solid medium was used and the cultures were inactivated with 0.02% thiomersal and by heating for 1 hour at 56°C. The final vibrio concentration of the vaccines was adjusted to 16 × 10⁹ vibrios/ml (equal proportions of the two serotypes). The antigenicity of the vaccines was assessed by the active mouse protection test and by the antibody production test, i.e. by determinating the vibriocidal antibodies in the sera of immunized mice. The results of the active mouse protection test showed that the antigenicity of the Inaba and Ogawa components of both vaccines met the WHO Requirements. The antigenicity of the Inaba component of both vaccines was about the same. The antigenicity of the Ogawa component of the plain vaccine appeared to be somewhat higher than that of the adsorbed vaccine. In the antibody production test, the adsorbed vaccine elicited a higher and longer-lasting immune response than the plain vaccine.     

Evaluation of typhoid vaccines in the laboratory and in a controlled field trial in Poland: Preliminary report

In 1961 a controlled field trial of anti-typhoid vaccines was carried out in 25 regions in Poland. Four types of vaccine were studied: (1) bacterial acetone-killed and -dried vaccine (two kinds), (2) bacterial formol-killed phenol-preserved vaccine, (3) Westphal''s endotoxin adsorbed on aluminium hydroxide, and (4) Grasset''s vaccine (autolysate of typhoid bacilli adsorbed on aluminium hydroxide). The control vaccine was tetanus toxoid. A total of 690 655 persons received two inoculations. Prior to the field trial, laboratory tests were carried out on the vaccines, postvaccinal reactions were studied, and a serological examination was made of randomly selected blood samples. The vaccination was followed by a two-year survey of cases of typhoid and other diseases. Among children aged 5-14 years, the formol-killed phenol-preserved vaccine was found to be the most effective and Grasset''s vaccine the least. Among adults aged 15-60 years, no conclusive evidence for the effectiveness of the vaccines could be obtained owing to the small number of cases. This may be due to the maintenance of immunity through repeated annual vaccination with bacterial vaccines.     

A randomised single blind trial of a combined mumps measles rubella vaccine to evaluate serological response and reactions in the UK population

Four hundred and twenty children were randomly assigned to receive either mumps measles rubella (MMR) vaccine (207) or measles vaccine (213) in a single blind study, to investigate the reactogenicity and serology of the MMR vaccine. There was no significant difference between the number of children developing symptoms after MMR vaccination to those developing symptoms after measles vaccination. Both vaccines are associated with a rash, temperature and restlessness five to thirteen days after vaccination. The serological response to measles vaccine was similar in both groups with 92-6% seroconverting with MMR, and 96-8% with measles. Seroconvertion against mumps and rubella with the MMR vaccine was 88% and 96% respectively. This study confirms the safety and efficacy of the MMR vaccine in a UK population.     

A controlled field trial to evaluate the protective capacity of a single dose of acetone-killed agar-grown and heat-killed broth-grown typhoid vaccines

In a strictly controlled field trial among schoolchildren a study was made of the protective capacity of single doses of 2 typhoid vaccines: a heat-killed broth-grown sorbed dried vaccine made in the USSR (vaccine G-66) and an acetone-killed agar-grown dried vaccine (vaccine K-66) made in Yugoslavia. The latter vaccine was supplied by the World Health Organization.     

Comparative trial of influenza vaccines. II. Adverse reactions in children and adults.

Commercially prepared zonally and chromatographically purified bivalent (A/England-B/Mass) and monovalent (B/Hong Kong) inactivated influenza vaccines were given to 438 individuals 6-33 years old. The vaccines had been examined for antigen content by chick cell agglutination (CCA) tests and electron microscopic particle count determinations. Endotoxin and pyrogen content were determined by limulus amebocyte lysate (LAL) and rabbit pyrogenicity assays; and egg-associated protein contamination was estimated by total protein and single radial immunodiffusion assays. Although great differences (10-200-fold) were found in the amount of endotoxin or pyrogen in the vaccines, no significant differences were found in the febrile responses they induced. Both bivalent and monovalent vaccines induced fever of greater than or equal to 38 C at a rate of approximately 3 1/2-4% above background. The febrile responses were most frequent at 24 hours after inoculation and a higher rate was observed in children than adults. Local reactions consisting of tenderness, erythema or induration were seen in from 20-57% of the recipients and also were unrelated to the pyrogenic or host-derived materials in the vaccines. Adults had higher local reaction rates than children and some vaccines containing larger amounts of viral antigen induced significantly higher rates of reactivity than did vaccines containing smaller amounts of antigen. Although 37-51% of all recipients experienced either a local and/or febrile reaction to influenza immunization, the reactions were in general mild and would not consitute a significant disadvantage in the immunization of children over 6 years and adults to prevent influenza infection and its sequelae.