Immunogenicity and safety of the human papillomavirus vaccine in young survivors of cancer in the USA: a single-arm, open-label, phase 2, non-inferiority trial.

BACKGROUND: Young survivors of cancer are at increased risk for cancers that are related to human papillomavirus (HPV), primarily caused by oncogenic HPV types 16 and 18. We aimed to examine the immunogenicity and safety of the three-dose series of HPV vaccine in young survivors of cancer. METHODS: We conducted an investigator-initiated, phase 2, single-arm, open-label, non-inferiority trial at five National Cancer Institute-designated comprehensive cancer centres in the USA. Eligible participants were survivors of cancer who were HPV vaccine-naive, were aged 9-26 years, in remission, and had completed cancer therapy between 1 and 5 years previously. Participants received three intramuscular doses of either quadrivalent HPV vaccine (HPV4; enrolments on or before March 1, 2016) or nonavalent HPV vaccine (HPV9; enrolments after March 1, 2016) over 6 months (on day 1, at month 2, and at month 6). We also obtained data from published clinical trials assessing safety and immunogenicity of HPV4 and HPV9 in 9-26-year-olds from the general population, as a comparator group. The primary endpoint was antibody response against HPV types 16 and 18 at month 7 in the per-protocol population. A response was deemed non-inferior if the lower bound of the multiplicity-adjusted 95% CI was greater than 0·5 for the ratio of anti-HPV-16 and anti-HPV-18 geometric mean titres (GMTs) in survivors of cancer versus the general population. Responses were examined separately in male and female participants by age group (ie, 9-15 years and 16-26 years). Safety was assessed in all participants who received at least one vaccine dose and for whom safety data were available. This study is registered with ClinicalTrials.gov, NCT01492582. This trial is now completed. FINDINGS: Between Feb 18, 2013, and June 22, 2018, we enrolled 453 survivors of cancer, of whom 436 received one or more vaccine doses: 203 (47%) participants had survived leukaemia, 185 (42%) were female, and 280 (64%) were non-Hispanic white. Mean age at first dose was 15·6 years (SD 4·6). 378 (83%) of 453 participants had evaluable immunogenicity data; main reasons for exclusion from per-protocol analysis were to loss to follow-up, patient reasons, and medical reasons. Data were also obtained from 26 486 general population controls. The ratio of mean GMT for anti-HPV types 16 and 18 in survivors of cancer versus the general population was more than 1 for all subgroups (ie, aged 9-15 years, aged 16-26 years, male, and female groups) in both vaccine cohorts (ranging from 1·64 [95% CI 1·12-2·18] for anti-HPV type 16 in female participants aged 9-15 years who received HPV9, to 4·77 [2·48-7·18] for anti-HPV type 18 in male participants aged 16-26 years who received HPV4). Non-inferiority criteria were met within each age and sex subgroup, except against HPV type 18 in female participants aged 16-26 years receiving HPV9 (4·30 [0·00-9·05]). Adverse events were reported by 237 (54%) of 435 participants; injection site pain was most common (174 [40%] participants). One serious adverse event (ie, erythema nodosum) was possibly related to vaccine (HPV9; 16-26 year female cohort). INTERPRETATION: Immunogenicity and safety of HPV vaccine three-dose series in survivors of cancer is similar to that in the general population, providing evidence for use in this clinically vulnerable population. FUNDING: US National Cancer Institute, Merck, Sharp & Dohme, and American Lebanese Syrian Associated Charities.

Evaluation of two sexual-stage antigens as bivalent transmission-blocking vaccines in rodent malaria.

BACKGROUND: Transmission-blocking vaccine (TBV) is a promising strategy for malaria elimination. It is hypothesized that mixing or fusing two antigens targeting different stages of sexual development may provide higher transmission-blocking activity than these antigens used individually. METHODS: A chimeric protein composed of fragments of Pbg37 and PSOP25 was designed and expressed the recombinant protein in Escherichia coli Rosetta-gami B (DE3). After immunizing mice with individual recombinant proteins Pbg37 and PSOP25, mixed proteins (Pbg37+PSOP25), or the fusion protein (Pbg37-PSOP25), the antibody titers of individual sera were analyzed by ELISA. IFA and Western blot were performed to test the reactivity of the antisera with the native proteins in the parasite. The transmission-blocking activity of the different immunization schemes was assessed using in vitro and in vivo assays. RESULTS: When Pbg37 and PSOP25 were co-administered in a mixture or as a fusion protein, they elicited similar antibody responses in mice as single antigens without causing immunological interference with each other. Antibodies against the mixed or fused antigens recognized the target proteins in the gametocyte, gamete, zygote, and ookinete stages. The mixed proteins or the fusion protein induced antibodies with significantly stronger transmission-reducing activities in vitro and in vivo than individual antigens. CONCLUSIONS: There was no immunological interference between Pbg37 and PSOP25. The bivalent vaccines, which expand the portion of the sexual development during which the transmission-blocking antibodies act, produced significantly stronger transmission-reducing activities than single antigens. Altogether, these data provide the theoretical basis for the development of combination TBVs targeting different sexual stages.

Improved immune responses to a bivalent vaccine of Newcastle disease and avian influenza in chickens by ginseng stem-leaf saponins.

Our previous investigation demonstrated that ginseng stem-leaf saponins (GSLS) derived from the stems and leaves of Panax ginseng C.A. Meyer promoted humoral and gut mucosal immunity in chickens vaccinated with live infectious bursa disease vaccine. The present study was designed to evaluate the effect of GSLS on the immune response to a bivalent inactive vaccine of Newcastle disease (ND) and avian influenza (AI) in chickens immunosuppressed by cyclophosphamide (Cy). One hundred and sixty-eight specific-pathogen-free (SPF) chickens were randomly divided into 7 groups, each containing 24 birds. Chickens in groups 3-7 received intramuscular injection of Cy at 100mg/kg BW for 3 days to induce immunosuppression. Groups 1 and 2 were injected with saline solution in the same way as groups 3-7. Following injection of Cy, groups 4-7 were orally administrated GSLS (2.5, 5 and 10mg/kg BW) or astragalus polysaccharide (APS) (200mg/L) in drinking water for 7 days; groups 1-3 were not medicated and served as control birds. After administration of GSLS or APS, groups 2-7 were subcutaneously injected with a bivalent inactive vaccine of ND and AI. After that, serum was sampled for detecting antibody titers by HI, spleen was collected for lymphocyte proliferation assay, and duodenum tissues were collected for measurement of IgA-secreting (IgA+) cells and intestinal intraepithelial lymphocytes (iIELs). The results showed that injection of Cy significantly suppressed immunity in chickens; oral administration of GSLS before immunization recovered splenocyte proliferation induced by ConA and LPS, and the numbers of IgA+ cells and iIELs as well as the specific antibody response to a bivalent inactive vaccine of ND and AIin immunosuppressed chickens treated with Cy. Therefore, GSLS may be the potential agent to improve vaccination in immunosuppressed chickens.

Preclinical development of a dengue tetravalent recombinant subunit vaccine: Immunogenicity and protective efficacy in nonhuman primates.

We describe here the preclinical development of a dengue vaccine composed of recombinant subunit carboxy-truncated envelope (E) proteins (DEN-80E) for each of the four dengue serotypes. Immunogenicity and protective efficacy studies in Rhesus monkeys were conducted to evaluate monovalent and tetravalent DEN-80E vaccines formulated with ISCOMATRIX™ adjuvant. Three different doses and two dosing regimens (0, 1, 2 months and 0, 1, 2, and 6 months) were evaluated in these studies. We first evaluated monomeric (DEN4-80E) and dimeric (DEN4-80EZip) versions of DEN4-80E, the latter generated in an attempt to improve immunogenicity. The two antigens, evaluated at 6, 20 and 100 µg/dose formulated with ISCOMATRIX™ adjuvant, were equally immunogenic. A group immunized with 20 µg DEN4-80E and Alhydrogel™ induced much weaker responses. When challenged with wild-type dengue type 4 virus, all animals in the 6 and 20 µg groups and all but one in the DEN4-80EZip 100 µg group were protected from viremia. Two out of three monkeys in the Alhydrogel™ group had breakthrough viremia. A similar study was conducted to evaluate tetravalent formulations at low (3, 3, 3, 6 µg of DEN1-80E, DEN2-80E, DEN3-80E and DEN4-80E respectively), medium (10, 10, 10, 20 µg) and high (50, 50, 50, 100 µg) doses. All doses were comparably immunogenic and induced high titer, balanced neutralizing antibodies against all four DENV. Upon challenge with the four wild-type DENV, all animals in the low and medium dose groups were protected against viremia while two animals in the high-dose group exhibited breakthrough viremia. Our studies also indicated that a 0, 1, 2 and 6 month vaccination schedule is superior to the 0, 1, and 2 month schedule in terms of durability. Overall, the subunit vaccine was demonstrated to induce strong neutralization titers resulting in protection against viremia following challenge even 8-12 months after the last vaccine dose.

Safety, immunogenicity, and antibody persistence following an investigational Streptococcus pneumoniae and Haemophilus influenzae triple-protein vaccine in a phase 1 randomized controlled study in healthy adults.

We investigated a protein-based nontypeable Haemophilus influenzae (NTHi) and pneumococcal (HiP) vaccine containing pneumococcal histidine triad D (PhtD), detoxified pneumolysin (dPly), and NTHi protein D (PD) in adults. In a phase I study, 40 healthy 18- to 40-year-old subjects were randomized (2:2:1) to receive two HiP doses administered 60 days apart, with or without AS03 adjuvant (HiP-AS and HiP groups, respectively), or Engerix B (GlaxoSmithKline, Belgium) as a control. Safety, antibodies, and antigen-specific CD4(+) T-cell immune responses were assessed before and until 480 days after vaccination. No serious adverse events were reported, and no subject withdrew due to an adverse event. Local and systemic symptoms were reported more frequently in the HiP-AS group than in the other two groups. The frequency and intensity of local and systemic symptoms appeared to increase after the second dose of HiP-AS or HiP but not Engerix B. Antibody geometric mean concentrations (GMCs) for PhtD, dPly, and PD increased after each dose of HiP-AS or HiP, with higher GMCs being observed in the HiP-AS group (statistically significant for anti-PD after dose 1 and anti-Ply after dose 2). GMCs remained higher at day 420 than prior to vaccination in both the HiP-AS and HiP groups. Antigen-specific CD4(+) T cells increased after each dose but were unmeasurable by day 480. Two doses of an investigational PhtD-dPly-PD protein vaccine induced humoral immunity and antigen-specific CD4(+) T-cell responses after each dose, with generally higher responses when the vaccine was administered with AS03. HiP combined with AS03 appeared to be more reactogenic than the antigens alone. (This study has been registered at ClinicalTrials.gov under registration no. NCT00814489.).

Neutral and acidic oligosaccharides supplementation does not increase the vaccine antibody response in preterm infants in a randomized clinical trial.

BACKGROUND: In preterm infants, a decreased immunological response and lower serological effectiveness are observed after immunizations due to ineffectiveness of both humoral and cellular immune mechanisms. OBJECTIVE: To determine the effect of 80% neutral oligosaccharides [small-chain galacto-oligosaccharides/long-chain fructo-oligosaccharides (scGOS/lcFOS)] in combination with 20% pectin-derived acidic oligosaccharides (pAOS) on antibody concentrations after DTaP-IPV-Hib immunization in preterm infants. DESIGN: In this randomized clinical trial, preterm infants with gestational age <32 weeks and/or birth weight <1500 g received enteral supplementation with scGOS/lcFOS/pAOS or placebo (maltodextrin) between days 3 and 30 of life. Blood samples were collected at 5 and 12 months of age. RESULTS: In total, 113 infants were included. Baseline and nutritional characteristics were not different in both groups. Geometric mean titers were not different after prebiotic supplementation at 5 months, Ptx (37/44 EU/ml), FHA (78/96 EU/ml), Prn (78/80 EU/ml), Diphtheria (0.40/0.57 IU/ml), Tetanus (0.74/0.99 IU/ml) and Hib (0.35/0.63 µg/ml), and at 12 months Ptx (55/66 EU/ml), FHA (122/119 EU/ml), Prn (116/106 Eu/ml), Diphtheria (0.88/1.11 IU/ml), Tetanus (1.64/1.79 IU/ml) and Hib (2.91/2.55 µg/ml). CONCLUSIONS: Enteral supplementation of neutral (scGOS/lcFOS) and acidic oligosaccharides (pAOS) does not improve the immunization response in preterm infants. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN16211826 ISRCTN16211826.

[Protective effect of the aerosol immunization of mice with the polycomponent vaccine Immunovac VP-4 after the challenge of the animals with Klebsiella pneumoniae virulent strain].

Used four schemes of the administration of the preparation with different time of the exposition of the animals in an aerosol chamber were tested with their subsequent intraperitoneal challenge with K. pneumoniae virulent strain K16. Irrespective of the number of immunization courses, the administration of the preparation made at intervals of 1 day, or daily, did not ensure any protective effect, but only led to an insignificant increase in their survival time in comparison with nonimmunized animals. After intervals between immunizations were increased to 3 days the protective effect of aerosol immumization was obtained (the survival rate was 65-80 % and considerably differed from that of the controls). The protective effect of aerosol immunization thus obtained was comparable with the effectiveness immunization made in a single subcutaneous injection. Aerosol immunization resulted in low antibody titers to the antigens contained in the vaccine, while after a single subcutaneous injection high antibody titers to Klebsiella and Proteus antigens were detected. The antigen-stimulated blast transformation of spleen lymphocytes in mice subjected to aerosol immunizations in 5 exposures was high. After subcutaneous immunization significant changes in such characteristics were detected on day 15. The data thus obtained were indicative of good prospects in the development Immunovac VP-4 as the medicinal form intended for use in aerosols.

Recombinant, live-attenuated tetravalent dengue virus vaccine formulations induce a balanced, broad, and protective neutralizing antibody response against each of the four serotypes in rhesus monkeys.

Three tetravalent vaccine (TV) formulations of previously described monovalent dengue (DEN) virus vaccine candidates were compared to a tetravalent formulation of wild-type DEN viruses (T-wt) for replication in SCID mice transplanted with human liver cells (SCID-HuH-7) or for replication and immunogenicity in rhesus monkeys. TV-1 consists of recombinant DEN1, -2, -3, and -4, each with a 30-nucleotide deletion in the 3' untranslated region (Delta30). TV-2 consists of rDEN1Delta30, rDEN4Delta30, and two antigenic chimeric viruses, rDEN2/4Delta30 and rDEN3/4Delta30, both also bearing the Delta30 mutation. TV-3 consists of rDEN1Delta30, rDEN2Delta30, rDEN4Delta30, and a 10-fold higher dose of rDEN3/4Delta30. TV-1 and TV-2 were attenuated in SCID-HuH-7 mice with minimal interference in replication among the virus components. TV-1, -2, and -3 were attenuated in rhesus monkeys as measured by duration and peak of viremia. Each monkey immunized with TV-1 and TV-3 seroconverted to the four DEN components by day 28 with neutralization titers ranging from 1:52 to 1:273 and 1:59 to 1:144 for TV-1 and TV-3, respectively. TV-2 induced low antibody titers to DEN2 and DEN3, but a booster immunization after 4 months increased the neutralizing antibody titers to greater than 1:100 against each serotype and elicited broad neutralizing activity against 19 of 20 DEN subtypes. A single dose of TV-2 induced protection against wild-type DEN1, DEN3, and DEN4 challenge, but not DEN2. However, two doses of TV-2 or TV-3 induced protection against DEN2 challenge. Two tetravalent formulations, TV-2 and TV-3, possess properties of a successful DEN vaccine and can be considered for evaluation in clinical trials.

Childhood and malaria vaccines combined in biodegradable microspheres produce immunity with synergistic interactions.

Biodegradable microspheres may represent a potential tool for the delivery of combination vaccines. We demonstrate strong immunogenicity of five co-encapsulated antigens after a single subcutaneous inoculation in guinea pigs. Tetanus- and diphtheria-specific antibodies were not significantly affected by the presence of either antigen or by the presence of pertussis or Haemophilus influenzae type b (Hib) antigens. Microsphere formulations gave better protection against diphtheria toxin than did two injections of a licensed tetravalent vaccine. Finally, a synthetic malaria peptide antigen (PfCS) also encapsulated in PLGA microspheres increased diphtheria and tetanus-specific immunity and improved protection against diphtheria. These findings demonstrate the potential of microspheres as an alternative and promising strategy for combination vaccines with a further aptitude in reducing the number of inoculations required to gain functional immunity.

Prelicensure evaluation of combination vaccines.

There is considerable public health interest in licensing safe and effective combination vaccines. Because combination vaccines may progress rapidly from phase 1 to a pivotal phase 2 immunogenicity trial, a rigorous approach to address product issues early in development is warranted. Clinical studies to evaluate the safety, immunogenicity, and (when necessary) clinical end point efficacy of combination vaccines should be randomized and well controlled in most cases. A large phase 3 safety study (i.e., a study that enrolls thousands of vaccinees) should be included in the development plan if a phase 3 (clinical end point) efficacy trial will not be conducted. Often, the new combination vaccine under development contains immunogens that have all been previously licensed, have demonstrated efficacy in earlier clinical trials, or both. For such products, comparative immunogenicity data may be sufficient to support efficacy. When applicable, clinical data to support simultaneous administration with other relevant vaccines should be obtained. Given the complexity of combination vaccine development, early consultation with United States Food and Drug Administration can be invaluable.

Making vaccines more acceptable--methods to prevent and minimize pain and other common adverse events associated with vaccines.

The growing abundance of highly immunogenic vaccines has arrived with a burden of pain, distress, and common adverse reactions that in turn may interfere with parental compliance and aggravate anti-vaccine sentiment. In a study of 150 children in each of 2 age-groups, we found that approximately 20% of the subjects suffered serious distress or worse. During the procedural phase, approximately 90% of the 15-to-18 month old children and 45% of the 4-to-6 year old children showed serious distress or worse. To address non-adherence with pediatric vaccine schedules, we must consider all of the possible issues that might prevent a parent from taking a child to a health care provider for vaccination. In that same study we identified useful predictors for both preparatory and procedural distress - predictors that might be used in identifying children who might benefit from preventive interventions. Vaccine providers might consider a variety of interventions. Attitude, empathy, instruction, and practice have all been shown to have a salutatory effect upon pain and anxiety with medical procedures in general and specifically with vaccinations. Distraction has also been found to be an effective method for distress and pain prevention in children. More formal methods of clinical hypnosis which combine a deep state of relaxation with focused imagery and suggestion have also been found to be effective in helping children and adolescents prepare for, cope with, and tolerate the pain and anxiety associated with medical procedures. So-called 'sugar nipples' delivering small amounts of sucrose orally at the time of a painful procedure in an infant has been not been shown to decrease vaccination pain and studies on refrigerant topical anesthetics are mixed. Studies have found a eutectic mixture of 2.5% lidocaine and 2.5% prilocaine (EMLA) effective in providing adequate local anesthesia in children, but it suffers from problems in practical application. Studies with various injection techniques have not identified ready solutions, and although jet injection appears to provoke less anxiety and cause less immediate pain, studies also indicate a somewhat greater incidence of delayed local reactogenicity including soreness and edema. Other measures to prevent or rapidly treat other common adverse events have been shown effective and should be considered as well.

Biological consequences of multiple vaccine and pyridostigmine pretreatment in the guinea pig.

An investigation of the possible interactions between combinations of vaccines and pyridostigmine bromide (PB) has been undertaken in the guinea pig. This study is part of a research programme funded by the UK Government to determine any effects of the pretreatment regimes given to UK Forces during the Persian Gulf conflict of 1990-1991. The study was designed to simulate PB administration and to model multiple vaccination protocols that were experienced by UK Forces, modelling a "worst case" situation in which all ten vaccines and PB were administered within a short period of time. Seven of the vaccines were health and hygiene (H+H) vaccines given to protect against endemic diseases and two vaccines to protect against the biological warfare agents anthrax and plague. In addition, pertussis vaccine was administered as an adjuvant to reduce the time to achieve immunity against anthrax. Four groups of eight animals were treated with 1/20th, 1/10th or 1/5th human doses of vaccines or vehicles, respectively. The PB or saline was delivered by implanted 28 day mini-osmotic pumps to achieve a mean red blood cell acetylcholinesterase (AChE) inhibition of around 30%. Body weight, temperature, immunological response, biochemical indices and spontaneous activity were monitored for 72 days. Although immunological responses to bacterial vaccines were observed, there were no remarkable findings in the parameters measured other than minor changes in body weight (4.9% decrease at the 1/5th human dose of vaccines) and temperature increases in response to vaccination. Animals in all groups remained generally healthy and active without visible adverse signs throughout the study. Reproduced with the permission of Her Majesty's Stationery Office. Published by John Wiley & Sons, Ltd.

Diphtheria in Lithuania, 1986-1996.

Diphtheria reappeared in Lithuania in 1986 and rose to epidemic levels by 1992. Between 1991 and 1996, 110 cases of diphtheria were registered, with an incidence of 0.03-1.15/100,000 population. Most cases (84%) and all 17 deaths occurred among persons >/=15 years, most of whom had never been vaccinated. Persons 40-49 years old had the highest average annual age-specific morbidity (1.70/100,000) and mortality (0.53/100,000) rates. Low levels of immunity among individuals 40-49 years old and migration to epidemic areas in Russia and Belarus contributed to the epidemic's occurrence. Between 1991 and 1995, toxigenic Corynebacterium diphtheriae strains were isolated from 84 of all registered patients (76%), and nontoxigenic strains were isolated from 13 (12%). By 1996, two mass vaccination campaigns, which provided one dose of vaccine to individuals 25-30 years old and three doses of vaccine to persons 31-60 years old, helped reduce the number of cases. The first campaign achieved 69% coverage; the second achieved 48% coverage.

Epidemic diphtheria in the Kyrgyz Republic, 1994-1998.

The Kyrgyz Republic experienced a widespread diphtheria epidemic during 1994-1998. National diphtheria surveillance and vaccination coverage information were used to describe the course of the epidemic. The epidemic began in August 1994, reached a peak in 1995 with 704 cases (incidence rate: 15.4/100,000 population) and 30 deaths, and declined to an incidence rate of 4.0/100,000 during the first 8 months of 1998. Age-specific incidence was highest in 1995 among persons 15-19 and 20-29 years old. Three rounds of mass vaccination with tetanus and diphtheria toxoids for adult use (Td) were conducted; reported coverage was 69% in 1995 and >95% in 1996 and 1997. Reported routine vaccination coverage with three doses of diphtheria toxoid by age 12 months increased from 62% in 1989 to 98% in 1997. Mass vaccination of the adult population with Td and improvements in childhood vaccination coverage played a major role in controlling the epidemic.

Diphtheria epidemic in the Republic of Uzbekistan, 1993-1996.

The Republic of Uzbekistan, like the other Newly Independent States in the 1990s, experienced epidemic diphtheria during the 1990s. The outbreak in Uzbekistan began in 1993 in southern regions that bordered areas of Tajikistan that were experiencing a very intense diphtheria epidemic. However, the Uzbek epidemic rapidly spread and threatened to involve the entire country. From 1993-1996, 1169 cases of diphtheria were reported, compared with 58 in 1990-1992. Unvaccinated or only partially vaccinated cases were more likely to have clinically severe forms of diphtheria than those who were fully vaccinated. Strong epidemiologic links with the Tajik diphtheria epidemic and the predominance of mitis biotype strains of Corynebacterium diphtheriae in Uzbekistan make it likely that the Uzbek outbreak arose independently of the predominantly biotype gravis epidemic that began in Russia. The epidemic appeared to be due to low population immunity and the large-scale reintroduction of toxigenic strains of C. diphtheriae. Several mass vaccination campaigns and general enhancement of routine immunization procedures led to control of the epidemic in 1996.

Seroepidemiological study of measles after the 1992 nationwide MMR revaccination program in Taiwan.

The incidence of measles declined rapidly in Taiwan after the introduction of the measles vaccine into the routine immunization schedule in 1978. However, an epidemic still occurred every 3-5 years until recently. A nationwide measles-mumps-rubella (MMR) revaccination program for school and preschool children has been in place since 1992 to control the indigenous transmission of measles. In order to understand the current immune status after this recent nationwide revaccination program, we determined the presence of measles IgG antibodies by enzyme-linked immunosorbent assay (ELISA) in 1,281 blood samples from healthy persons aged from 2 months to above 30 years collected between 1993 and 1995, and also in another batch of 90 sera samples from children aged 2 years collected before 1992. The results showed that 1) the measles antibody seropositive rate (36.4%) was lowest in children aged 5-7 months and rose to an unexpectedly high level of 85.8% at the age of 12-14 months, 2) the seropositive rate rose further to between 85.9% and 95.1% after 2 years of age and remained high in adults and pregnant women, and 3) the seropositive rate of the 2-year-old children collected before 1992 was 61.4%, which was significantly lower than the rate of the same age group collected after the nationwide MMR revaccination program. We conclude that the national revaccination program has promoted effectively measles immunity in Taiwan. This immunity explains the rarity of reported measles cases since the last epidemic in 1989. This revaccination program should continue and be extended to all preschool children and young adults so that indigenous measles can be eliminated by the year 2000.

Booster vaccination against diphtheria and tetanus in man. Comparison of three different vaccine formulations--III.

Adverse reactions and antibody levels were compared following a booster vaccination of 177 Danish military recruits with a plain, an aluminium hydroxide (0.5 mg Al per human dose, HD) and a calcium phosphate (0.25 mg Ca per HD) adsorbed diphtheria-tetanus (D-T) vaccine. The calcium phosphate adsorbed vaccine was given in a HD of 3 Lf of D and T toxoids and proved to be of equal efficacy as the aluminium hydroxide adsorbed vaccine which was injected in a dose containing twice the antigen amount. The calcium phosphate vaccine caused fewer adverse reactions than the one adsorbed to aluminium hydroxide. The plain vaccine (6 Lf per HD of D and T toxoid) had the highest efficacy with a similar low occurrence of adverse reactions as the calcium phosphate adsorbed vaccine. Potency assays in mice were in accordance with these immunogenicity results in man if a two dose immunization schedule was followed, but not if the vaccines were compared after a single immunization as requested by the procedure for potency testing according to current WHO and European Pharmacopoeia requirements. Both of the adsorbed vaccines primed mice for specific IgE antibody formation. This could be detected after a second immunization with either of the adsorbed vaccines or with the plain D-T vaccine. Also in humans, immunization with the plain vaccine boosted specific IgE formation to a detectable level. This may be ascribed to adjuvant priming during the primary vaccination series some 20 years previously.

Oral immunization against diphtheria and tetanus infections by fluid diphtheria and tetanus toxoids.

Purified diphtheria toxoid incorporated in egg yolk and mixed with a medicinal plant seed was used to orally immunize rabbits against diphtheria infection. Animals were partially immunized against a lethal diphtheria toxin challenge. The immunity was complete when gastric enzyme juices were inhibited before oral vaccination by aprotinin, a natural protease inhibitor. Rabbits and monkeys were orally immunized against both diphtheria and tetanus in the same way by pre-treatment with aprotinin. Adult volunteers receiving protease inhibitor before administration of oral toxoids have shown a significant rise in specific circulating antitoxins.