Rosemarie Berger

Vaccination of immunocompetent elderly subjects with a live attenuated Oka strain of varicella zoster virus : a randomized, controlled, dose-response trial

After primary infection in childhood, varicella zoster virus (VZV) remains latent in the dorsal route ganglia. Its reactivation later in life can lead to a zoster episode. VZV-specific, T-cell-mediated immunity (VZV-CMI) is likely to be important in preventing symptomatic reactivation. As CMI declines with age, a vaccine enhancing VZV-CMI might be effective in decreasing the incidence or severity of zoster in elderly subjects. A randomized, double blind controlled trial assessing CMI responses of elderly subjects immunized with a live attenuated, VZV-Oka vaccine was conducted. Two hundred healthy volunteers (55-75 years of age) received either a single injection of the VZV vaccine (PMC), containing 3200 (Oka 3200), 8500 (Oka 8500), or 41,650 (Oka 41650) PFU of live VZV, or a pneumococcus vaccine control group (Pneumo 23((R)). The immune response to VZV was assessed by measuring the T-cell response to VZV antigens, i.e. proliferation (stimulation index, SI), precursor cell frequency (PCF), cytokine secretion, and antibody titers. Six weeks post-vaccination, VZV-specific SI (adjusted mean values) was significantly greater (P<0.0001) in the 3 vaccine groups (with SI=5. 6 for Oka 3200; SI=5.0 for Oka 8500, and SI=7.2 for Oka 41,650) than in the control group (SI=2.9). The increase in PCF was striking, with 72.4, 91.2 and 85.1 precursors per million cells respectively in these 3 vaccine groups, vs 26.3 in the control group. No significant IL-4 secretion was observed in any subject, whereas the presence of IFN-gamma secretion was found to correlate with good responder status. The increase of these CMI parameters did not depend upon the titer of virus injected. Geometric mean titers of VZV antibodies increased in all vaccine groups and remained unchanged in the control group. Nevertheless, no correlation between the antibody response and the cell-mediated response was found. Live attenuated VZV vaccine caused a significant increase in VZV-CMI in a healthy, elderly population. No relationship between vaccine dose and the intensity of the specific response was found.

A single vaccination with an inactivated hepatitis A liposome vaccine induces protective antibodies after only two weeks

In the near future an inactivated hepatitis A vaccine will be commercially available. The recommended vaccination schedule will include at least two vaccinations 1 month apart. Giving two doses of vaccine on the same day in one injection results in protection after 2-4 weeks dependent on the adjuvant used. Hepatitis A virus incorporated into liposomes proved to be a suitable formulation in term of rapid seroconversion, high level of mean antibody content and low reactogenicity.

Virosomes as carriers for combined vaccines

Immunopotentiating reconstituted influenza virosomes (IRIV) are liposomes which carry the two glycoproteins of the influenza virus on their surface. A hepatitis A vaccine using IRIV as carrier has very good immunogenicity and is well tolerated. The objective of this study was to produce a fivefold combined vaccine against hepatitis A and B, diphtheria, tetanus and influenza A/B, and to show that in principle IRIVs can serve as carriers for multiple antigens which have good immunogenicity and are well tolerated. A total of four studies were carried out. Either the combined vaccine or the corresponding adequately tested alum-adsorbed single vaccines were tested for reactogenicity and immunogenicity in young adults. A hepatitis A and B combination on an IRIV base showed the same immunogenicity and toleration as the single vaccines. However, with the simultaneous coupling of all five vaccines on the same IRIV or the binding of Di-Te and HAV on different IRIVs there was a suppression of the humoral immune response against HAV (p = 0.03). The possibility that epitope-specific suppression had occurred could be ruled out. The suppression of the response against HAV could be circumvented by halving the quantity of Di-Te antigen in the combined vaccine so as to avoid antigenic competition. Surprisingly, the immunogenicity of Di-Te vaccination in the combination proved superior to that of a separate vaccination. All vaccinations were well tolerated.

Persistence of antibodies after immunization with a recombinant yeast-derived hepatitis B vaccine following two different schedules

Four years after vaccination of healthy adults with either a recombinant yeast-derived (YDV) or plasma-derived (PDV) hepatitis B vaccine, the persistence of antibodies to hepatitis B surface antigen (anti-HBs) was examined. Subjects received three 20 micrograms doses in the deltoid region according to either a 0, 1, 6 month or 0, 1, 2 month vaccination schedule, with a 20 micrograms booster dose of YDV administered at month 12 for subjects on the second schedule. The recombinant vaccine was found to be immunologically comparable to the PDV, with anti-HBs persisting equally in both groups.

A dose-response study of a live attenuated varicella-zoster virus (Oka strain) vaccine administered to adults 55 years of age and older

Decreased cell-mediated immune (CMI) response to varicella-zoster virus (VZV) is correlated with an increased risk of reactivation of latent virus from dorsal root sites, leading to herpes zoster. The cell-mediated and humoral immunogenicity of three concentrations (3200, 8500, and 41,650 pfu/dose) of a live attenuated VZV vaccine (Oka strain; VZV/Oka) was compared with a control pneumococcal polysaccharide vaccine in 200 healthy adults who were > or = 55 years old. Six weeks after vaccination, the VZV-specific CMI response (as measured by stimulation index values and precursor cell frequencies) was enhanced in all VZV/Oka vaccine groups compared with the control group (for all VZV/Oka groups combined vs. controls, tested with VZV crude antigen: stimulation index, P < .001; precursor cell frequency, P < .001). Geometric mean titers of anti-VZV antibodies increased in all VZV/Oka vaccine groups but remained unchanged in the control vaccine group. No dose effect of VZV/Oka vaccine was observed for CMI or humoral responses.

Time course of hepatitis A antibody production after active, passive and active/passive immunisation: The results are highly dependent on the antibody test system used

Two commercially available automated test systems for hepatitis A antibody, HAVAB IMX (Abbott) and ENZYMUN Anti-HAV (Boehringer) were evaluated in a study of active, passive and active/passive immunisation against hepatitis A. The inactivated hepatitis A vaccine Epaxal Berna and the hepatitis A immunoglobulin preparation Globuman were products of the Swiss Serum and Vaccine Institute. Although both hepatitis A antibody test kits were standardised with the same international WHO standard hepatitis A immunoglobulin preparation, divergent results were obtained for the level of circulating hepatitis A antibody after vaccination. One month after the vaccination the mean geometric antibody titres were 315 mIU/ml after active, 253 mIU after active/passive and 22 mIU after passive immunisation when measured with the Enzymun assay. In the same sera 70 mIU/ml after active, 60 mIU after active/passive and 18 mIU after passive immunisation could be detected with the IMX test. Antibody avidity studies could not explain the differences obtained by the two test methods. The neutralization test is the standard method for the estimation of protection against hepatitis A. This test is not suitable for large series of serum samples, and enzyme immunoassays are indispensable for vaccination studies. To be suitable for monitoring antibody development in phase I and II clinical trials as well as in postmarketing studies, EIA tests for hepatitis A antibodies must be commercially available and of known sensitivity. The Enzymun anti-HAV test developed by Boehringer Mannheim (Germany) offers the possibility to measure antibody titres around the protective level of 20 mIU/ml which is reached by the passive immunisation with immunoglobulin preparations or within two weeks after active vaccination with an inactivated hepatitis A vaccine. The Abbott IMX test system is more useful for the detection of natural infections by the hepatitis A virus.

Interference between strains in live virus vaccines II: combined vaccination with varicella and measles-mumps-rubella vaccine

A combined vaccine against varicella and measles-mumps-rubella made by mixing two commercially available products (Varilrix and Pluserix SK-RIT) has proved to be only partially successful in early trials. Although the seroconversion rates with the MMR components were comparable with those usually achieved, the varicella take was depressed to 77%. A new low dose measles-mumps-rubella vaccine was prepared in which the measles virus content was reduced to 1/5 and the mumps virus content to 1/8. Commercial varicella vaccine was added to the low dose MMR vaccine. The seroconversion rates for measles was 98.2%, for mumps 100%, for rubella 99.4% and for varicella 98%. This product seemed to be well balanced in respect of a possible interference between the four different virus vaccine strains.

Effects of interferons on immune response to a synthetic peptide malaria sporozoite vaccine in non-immune adults

A Plasmodium falciparum sporozoite vaccine, composed of a synthetic dodecapeptide (NANP)3 coupled to tetanus toxoid (TT), was injected, at weeks 0 and 8, into non-immune volunteers in two randomized double-blind placebo-controlled trials. In the first trial, 37 volunteers received the vaccine simultaneously with placebo (group 1), 0.5 x 10(6-) (group 2), or 1.5 x 10(6) U (group 3) of recombinant human interferon-alpha (= IFN-alpha). In the second trial, 35 other volunteers received the vaccine with placebo (group 4), 0.25 x 10(6) (group 5), or 1.0 x 10(6) IU (group 6) of interferon-gamma (= IFN-gamma). Immunizations were well tolerated and resulted in seroconversion rates (greater than or equal to 4-fold increase of antibody titre in immunofluorescence or enzyme-linked immunosorbent assays) of 67-100% of volunteers. IFN-alpha significantly enhanced the IgG antibody titres in ELISA to malaria peptide.

Inadequate response to intradermal hepatitis A vaccine

To assess the efficacy of the intradermal route of administration of hepatitis A vaccine we conducted a study in hospital laboratory workers. Forty-three volunteers were given three different combinations of intradermal and intramuscular hepatitis A vaccine and compared with 18 controls given intramuscular vaccine only. The geometric mean titres (GMT) after one, two and three intradermal doses of 0.1 ml each were 4.5, 28 and 143 IU l-1 respectively. The GMT after one intramuscular dose in the controls was 163 IU l-1. The results indicate that the response to intradermal hepatitis A vaccine is poor and its use cannot be recommended.

Interference between strains in live virus vaccines I: combined vaccination with measles, mumps and rubella vaccine

One to four different lots of four commercially available trivalent measles-mumps-rubella vaccines were tested for their efficacy as measured by the induction of antibodies to the three vaccine viruses. All of the products were satisfactory although a 100% seroconversion rate was attained regularly only with rubella vaccine. The live virus in the different measles and mumps vaccine components and especially the relative amounts of measles to mumps virus varied widely. Obviously, the efficacy of a vaccine should not be judged only by the virus content. Of main importance is the further adjustment of the dosage of the interfering vaccine virus strains in relation to their attenuation.