Immunoenhancement with combined rabies and aluminium-adjuvanted tetanus vaccines.

The effect of combining tetanus toxoid in the same syringe with purified Vero cell rabies vaccine (PVRV) was investigated in the 2-1-1 regimen of PVRV. The 2-1-1 regimen alone was as immunogenic as the five-dose regimen, while saving one dose of vaccine and two clinic visits. When aluminium hydroxide-adsorbed tetanus toxoid was used to dissolve PVRV on days 0 (one of the two doses) and 21, the anti-rabies antibody was significantly increased. Aluminium-free tetanus toxoid was ineffective, suggesting that immunoenhancement was due to aluminium adjuvant. In addition, anti-tetanus antibody was unaffected and the side-effects were not increased by such mixing.

The present status of rabies vaccine development and clinical experience with rabies vaccine.

Attempts to control human rabies have a long history: animal and human vaccines provide efficient weapons for prevention. In this presentation, we would like to consider the different rabies vaccines available for human use, and particularly the modern vaccines produced in cell culture. Rabies virus is considered as an unique virus, but in fact, 5 groups of rabies fixed strains are used throughout the world to produce human rabies vaccines: Pasteur, Beijing, Flury, Fuenzalida and SAD strains. The Pasteur-derived strains, designated PV or PM, are the most widely used for the production of traditional vaccines of the Semple or Suckling Mouse Brain (SMB) types, but also for the production of modern cell culture vaccines: Human Diploid and Purified Vero Cell vaccines (HDCV and PVRV). The different rabies vaccines should be classified according to the cell system used to cultivate the virus: animal systems are still employed to produce the old traditional vaccines-Semple and SMB-which continue to be produced in several countries; Primary cell systems, particularly Hamster Kidney and Chick embryo cells, are used; Cell lines are presently the most interesting approach for vaccine production. The use of the human diploid cell system permitted the development of the HDCV, the most widely distributed cell culture rabies vaccine, and today considered as the reference vaccine. The heteroploid VERO cell line was introduced in 1982 to the production of inactivated rabies vaccine; it retained all the advantages of the Human Diploid Cell system, while offering the possibility of the large scale industrial production of PVRV. For both HDCV and PVRV, production security is guaranteed by the existence of a master cell seed and working cell bank, with a complete history of the cell, a limited number of passages and permanent and total quality control of the cell substrate. The principal human rabies vaccines produced worldwide at present using cell culture are compared, in terms of their technical characteristics and their capacity economically to face worldwide vaccine needs. The greatest needs are today in tropical countries, where only a limited amount of modern cell culture vaccines are used.

Experience with preexposure rabies vaccination.

Preexposure rabies vaccination, presently limited to high-risk target populations, is facilitated by cell culture vaccines. Officially recommended programs comprise either two doses administered on days 0 and 28 or three doses given on days 0, 7, and 21 or 28. A first booster 1 year later ensures a good duration of immunity; follow-up studies now cover 5-8 years. These results were obtained by the intramuscular and subcutaneous injection routes; intradermal programs have been explored with the aim of reducing costs. Preexposure immunization is well tolerated, despite some systemic allergic reactions. Efficacy has been observed universally, but certain factors may affect results. Several lines of evidence favor an extension of preexposure vaccination. In Scandinavian countries, the majority of vaccine doses are used preexposure, while about 40%, 15%, and 10% are so used in the United Kingdom, the United States, and France, respectively. However, preventive immunization is rare in developing countries, where the risk of infection is maximal and permanent. The more economical new vaccines, such as purified Vero rabies vaccine, permit a reevaluation of preventive vaccination. Vaccine combinations including rabies may prove economical.

Persistence of rabies antibody 5 years after pre-exposure prophylaxis with human diploid cell antirabies vaccine and antibody response to a single booster dose.

In 1978, 22 staff members of the National Institute of Virology, Pune, India, were given two doses of human diploid cell antirabies vaccine (HDCV) for primary pre-exposure prophylactic immunization; the interval between the two doses being approximately 4 weeks. Eighteen of these 22 vaccinees were given a booster dose 1 year later. All 18 vaccinees developed protective levels of antibody; most of them had antibody levels exceeding 10 IU/ml. In 1984, 5 years after the booster dose, 11 (79.0%) of 14 vaccinees tested still possessed neutralizing antibody levels ranging from 0.5 IU/ml to 10 IU/ml. Fourteen days after the administration of a booster dose, the antibody levels ranged from 10 to greater than or equal to 100 IU/ml for all except one vaccine (5.2 IU/ml). These findings demonstrate that the majority of vaccines retained detectable neutralizing antibody after pre-exposure prophylaxis for as long as 5 years and that a single booster dose thereafter evoked a good antibody response.

Use of a combined DTP-polio vaccine in a reduced schedule.

A five-year serologic follow-up and a four-year monitoring of the polio and pertussis morbidity in an area immunized with a 2 + 1 dose schedule of a combined DTP-Po vaccine have shown that: the individual protection against polio measured by the presence of neutralizing antibody persists at a very adequate level five years after the first booster; after three years of a steady high proportion of children with pertussis antibody, a considerable drop is observed and in about 28% of individuals agglutinin levels of less than 1:20 were found five years after booster; the community protection against paralytic poliomyelitis and pertussis is satisfactory up to four years after the introduction of the program. Continuation of immunization with a 2 + 1 dose schedule at a maximal coverage and close seroepidemiologic surveillance are necessary in order to draw definite conclusions, because of the potentially strong impact of very dynamic ecological factors present in our geopolitical area upon the agent-host interrelationship.

[Antipoliomyelitis vaccination of young children with a new inactivated vaccine. Serological results]. / Vaccination antipoliomyélitique de jeunes enfants par un nouveau vaccin inactivé. Résultats sérologiques.

An inactivated trivalent poliovirus vaccine, prepared on simian line-cells (Vero cells), has been injected in 3 doses one month apart in 36 infants, 2 to 11 months old (30 of whom were 2 to 6 months old) to determine its tolerance and antigenic efficacy. Each dose contained 40, 8 and 32 antigenic D units for the 3 types respectively. DPT vaccine was injected simultaneously in another part of the body. Before beginning the immunization program, 20 infants had significant titers of antibodies against the 3 types of poliovirus; Only 6 were triple negative. One month after the second dose of vaccine, all the infants had significant titers of antibodies against the 3 types; these titers have not been significantly enhanced one month after the third dose. Two doses of the inactivated vaccine one month apart induced a satisfactory serologic response in spite of the presence of serum maternally transmitted antibodies. There were no adverse reactions.

A modified schedule for routine pertussis immunization.

As part of a study with a quadruple inactivated vaccine (diphtheria-pertussis-tetanus-polio), the serologic response to the pertussis antigen was investigated in infants at the age of routine immunization, inoculated with one of the following two regimens: either 0.5 ml vaccine at 2 and 3 1/2 months and a booster six months later, or an identical dose of vaccine given at 2, 4 and 6 months and a booster at the age of 12 months. A pertussis agglutination titer of greater than or equal to 1:10 was considered an immune response to the administration of the antigen. Two basic doses of pertussis antigen induced an immune response in about 92% of children, which was very close to that following three basic doses. A 100% seroconversion was observed in both groups one month after the booster dose, and geometric mean values were high in both regimens. At one and two years after the booster, the pertussis agglutinins were present in 100% of children of both groups, with higher geometric mean values in the group given the three basic doses regimen.

Pertussis immunization of infants using a new combined DTP-polio vaccine.

As part of the evaluation of a new combined Diphtheria-Tetanus-Pertussis-Poliomyelitis (DTP-Polio) inactivated vaccine, the pertussis agglutinin response was studied in 62 infants, two to three months old. Each dose of vaccine combined these antigens in a 0.5 ml volume, and contained at least four International Protective Units of pertussis antigen adsorbed on aluminium hydroxide. Infants were vaccinated with three doses of DTP-Polio vaccine at two month intervals. Pertussis agglutinin determinations showed a satisfactory response after two DTP-Polio vaccine doses. Although higher agglutinin titres were apparent after three doses than after two, no significant difference was observed in the seroconversion rate after two or three doses (88.8% and 96.3% respectively). The DTP-Polio vaccine would thus seem suitable for use in a two-dose primary immunization schedule against pertussis.

Seroimmunity following vaccination in infants by an inactivated poliovirus vaccine prepared on Vero cells.

An inactivated poliovirus vaccine prepared from cultures of Vero cells has been tested on 61 infants from two to 11 months of age (mean age, 4.3 months) for tolerance and serologic potency. Three doses of vaccine were given one month apart at the same time that diphtheria-tetanus-pertussis vaccine was injected at another body site. Poliovirus-neutralizing antibody titers were measured before the first and third injections and one month after each. The titer was considered positive when the dilution was greater than or equal to 1:4. The tolerance has been good. Thirty-one infants were assessable for serologic efficacy; all had significant serologic responses after two injections of polio vaccine, regardless of the titer of maternally transmitted antibodies before the immunizations. The third injection did not significantly increase the antibody titer observed after the first two doses.

Multitest CMI for standardized measurement of delayed cutaneous hypersensitivity and cell-mediated immunity. Normal values and proposed scoring system for healthy adults in the U.S.A.

The Multitest CMI system, a disposable device that simultaneously applies seven standardized preloaded antigens and diluent control, is a major advance for measurement of delayed type hypersensitivity (DTH) in assessment of cell-mediated immunity (CMI). The system was tested in 402 healthy adults, aged 17 to 92 years, to determine normal values for incidence and size of DTH responses. Incidence of positive responses to individual antigens varied from 85% to 46%, with great variability related to age and sex. To better assess CMI, a two-part score based on 48-hour readings was employed. The mean number of positive antigens ranged between four and five, and the mean sum of their mm induration ranged between 18 and 25, with both scores increasing with advancing age. A statistical zone of reduced DTH scores (hypoergy) was identified. The Multitest CMI system appears to be a practical means of reproducibly assessing CMI in subjects with immunologic, metabolic, infectious, or neoplastic disorders. The scores in our population may serve as reference values to which results from any tested adult can be compared.

[Cutaneous delayed hypersensitivity in a French reference population using the cell-mediated immunity multitest device]. / Etude sur une population française de référence de l'hypersensibilité cutanée retardée par le dispositif multitest I.M.C.

The authors present a disposable device which may be used for skin tests studying delayed cellular hypersensitivity with 7 antigens and a glycerin control. With the aim of more objective evaluation of the results, they suggest the establishment of a score taking into account the number of positive reactions and the degree of the reactions. Finally, they describe the results of a large multicentre study involving 830 subjects considered to be healthy and divided into 4 groups according to the response to the tests.