Showing papers in "Human Vaccines in 2009"

Comparison of the immunogenicity and safety of Cervarix™ and Gardasil® human papillomavirus (HPV) cervical cancer vaccines in healthy women aged 18–45 years

Abstract: This observer-blind study compared the prophylactic human papillomavirus (HPV) vaccines, Cervarix (GlaxoSmithKline) and Gardasil (Merck), by assessing immunogenicity and safety through one month after completion of the three-dose vaccination course. Women (n = 1106) were stratified by age (18-26, 27-35, 36-45 years) and randomized (1:1) to receive Cervarix (Months 0, 1, 6) or Gardasil (Months 0, 2, 6). At Month 7 after first vaccination, all women in the according-to-protocol cohort who were seronegative/DNA negative before vaccination for the HPV type analyzed had seroconverted for HPV-16 and HPV-18 serum neutralizing antibodies, as measured by pseudovirion-based neutralization assay (PBNA), except for two women aged 27-35 years in the Gardasil group who did not seroconvert for HPV-18 (98%). Geometric mean titers of serum neutralizing antibodies ranged from 2.3-4.8-fold higher for HPV-16 and 6.8-9.1-fold higher for HPV-18 after vaccination with Cervarix compared with Gardasil, across all age strata. In the total vaccinated cohort (all women who received at least one vaccine dose, regardless of their serological and DNA status prior to vaccination), Cervarix induced significantly higher serum neutralizing antibody titers in all age strata (p or= 84%) for both vaccines. Although the importance of differences in magnitude of immune response between these vaccines is unknown, they may represent determinants of duration of protection against HPV-16/18. Long-term studies evaluating duration of efficacy after vaccination are needed for both vaccines.

Evaluation of quadrivalent HPV 6/11/16/18 vaccine efficacy against cervical and anogenital disease in subjects with serological evidence of prior vaccine type HPV infection.

Abstract: ObjectiveIn the quadrivalent (types 6/11/16/18) HPV vaccine (GARDASIL®/SILGARD®) clinical program, 73% of women aged 16-26 were naive to all vaccine HPV types. In these women, prophylactic administ...

Safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine for cervical cancer prevention: a pooled analysis of 11 clinical trials.

Abstract: A pooled analysis of the safety of the human papillomavirus (HPV)-16/18 AS04-adjuvanted cervical cancer vaccine Cervarix (GlaxoSmithKline) was performed in a cohort of almost 30,000 girls and women aged > or =10 years, 16,142 who received at least one dose of the HPV-16/18 vaccine and 13,811 who received one of three controls [Al(OH)(3) or hepatitis A vaccine (720 or 360 EU)] Data are available for a total of 45,988 vaccine doses Solicited local and general symptoms were recorded for seven days after each dose Serious adverse events (SAEs), pregnancies, medically significant conditions (MSCs) and new onset of chronic diseases (NOCDs), including new onset of autoimmune diseases (NOADs), were proactively monitored Data were analyzed by vaccine group according to age (10-14, 15-25 and >25 years) and reporting period (months 0-7, months 7-12 and >month 12) Rates of solicited local and general symptoms were higher in the HPV-16/18 vaccine group than in the control groups However, compliance with the three-dose schedule was high and did not differ between groups (934% for HPV-16/18 vaccine group versus 925% for pooled controls) No clinically relevant differences were seen between the HPV-16/18 vaccine and pooled control groups in rates of SAEs (28% versus 31%), MSCs (194% versus 214%), NOCDs (17% in both groups) or NOADs (04% versus 03%) Similarly, no differences in pregnancy outcomes or rates of withdrawals due to AEs or SAEs were observed between groups In conclusion, analysis of this large database shows the HPV-16/18 AS04-adjuvanted cervical cancer vaccine to have a favorable safety profile in women of all ages

BCG vaccines: their mechanisms of attenuation and impact on safety and protective efficacy.

Abstract: Mycobacterium bovis Bacille Calmette-Guerin (BCG) was developed as an attenuated live vaccine for tuberculosis control nearly a century ago. Despite being the most widely used vaccine in human history, the mechanisms of attenuation of BCG remain poorly understood. BCG is not a single organism, but comprises a number of substrains that differ in genotypes and phenotypes. The impacts of these differences on BCG vaccine properties are largely unknown. Nevertheless, in the past decade, the development of sophisticated genome analysis techniques, coupled with advances in knowledge of the virulence mechanisms of Mycobacterium tuberculosis, have provided greater insights into the attenuation and evolution of BCG. This review article discusses these new developments, focusing on molecular mechanisms that contribute to the attenuation of BCG substrains. It is evident that BCG strains comprise natural mutants of major virulence factors of M. tb, including ESX-1, PDIM/PGL and PhoP, and that BCG substrains differ markedly in virulence level. The impacts of these findings on vaccine properties including adverse reaction effect, tuberculin reactivity and protective efficacy are discussed. These new insights have extremely important implications for national immunization programs and the development of future vaccines.

Phase 2 clinical trial of three formulations of tetravalent live-attenuated dengue vaccine in flavivirus-naïve adults.

Abstract: Sixteen dose formulations of our live-attenuated tetravalent dengue virus vaccines (TDV) were previously evaluated for safety and immunogenicity. Two of the sixteen candidate TDV formulations (Formulations 13 and 14) were selected for further evaluation. A new TDV formulation, Formulation 17, using a higher primary dog kidney (PDK) cell passage Dengue-1 virus (DENV-1) and a lower PDK cell passage DENV-4, was developed to optimize the neutralizing antibody response. All three formulations consist of combinations of 10exp3-5 pfu/dose of the four dengue vaccine virus serotypes. This double-blind, randomized trial in 71 healthy adult subjects evaluated vaccine safety, reactogenicity and immunogenicity. TDV's were given subcutaneously in the deltoid on Day 0 and 180 (6 months). Subjects were seen in clinic on Study Days 0, 10, 28, 180, 190 and 208 and filled out daily symptom diaries for 21 days after each vaccination. Formulation 13 was the most reactogenic, while both Formulations 14 and 17 were similar in reported reactions. Seventy-five percent, 31% and 31% of subjects were viremic on Day 10 after primary vaccination with Formulations 13, 14 and 17 respectively. Viremia was not detected in any subject following the second dose of vaccine. The immunogenicity endpoint was neutralizing antibody titer one month after the second vaccination. Thirty-six percent, 40% and 63% of vaccinated subjects developed tetravalent neutralizing antibodies after two doses of Formulations 13, 14 and 17, respectively. Formulation 17 was selected for further clinical evaluation based on this study.

Priming of CD4+ and CD8+ T cell responses using a HCV core ISCOMATRIX vaccine: a phase I study in healthy volunteers.

Abstract: The disease burden and public health impact of chronic HCV infection continues to be a major problem globally. Current treatment for chronic HCV infection is not effective in all patients and is frequently associated with unacceptable side effects. Clearly a need exists for improved treatments and one such strategy is the use of therapeutic vaccines. Although still not completely understood, emerging data indicate that the generation of CD4(+) and CD8(+) T cells are important for the clearance of HCV. We have developed a prototype vaccine with the HCV Core protein and ISCOMATRIX adjuvant (HCV Core ISCOMATRIX vaccine). ISCOMATRIX vaccines have been shown to induce CD4(+) and CD8(+) T cell responses to a range of antigens in both animal models and in human studies. Additionally, ISCOMATRIX vaccines have been shown to be safe and generally well tolerated in several clinical trials. Preliminary studies demonstrated that the prototype HCV Core ISCOMATRIX vaccine induced strong CD4(+) and CD8(+) T cell responses in monkeys following immunization. Here we show the results of a Phase I placebo controlled, dose escalation clinical study designed to evaluate the safety, tolerability and immunogenicity of the HCV Core ISCOMATRIX vaccine in healthy individuals. The 30 subjects received three immunizations of HCV Core ISCOMATRIX vaccines or placebo vaccine on days 0, 28 and 56. The HCV Core ISCOMATRIX vaccines contained 5, 20 or 50 microg HCV Core protein with 120 mug ISCOMATRIX adjuvant. The adverse events reported were generally mild to moderate in severity, of short duration and self-limiting. The most common adverse events were injection site reactions such as pain and redness as well as myalgia. Antibody responses were detected in all but one of the participants receiving the HCV Core ISCOMATRIX vaccine and there was no indication of a dose response. CD8(+) T cell responses were only detected in two of the eight participants receiving the highest dose. T cell cytokines were detected in 7 of the 8 participants in the highest dose group. The results of this study support the further evaluation of this prototype HCV Core ISCOMATRIX vaccine in HCV infected subjects.

The candidate tuberculosis vaccine Mtb72F/AS02A: Tolerability and immunogenicity in humans.

Abstract: Tuberculosis (TB) remains uncontrolled in many parts of the world and the development of an effective vaccine against TB represents a high priority unmet medical need. Healthy PPD (tuberculin purified protein derivative)-negative adult volunteers, aged 18-40 years received three doses of the candidate Mtb72F/AS02A vaccine according to a 0-1-2 months schedule in an open-label Phase I study (NCT00730795). Solicited, unsolicited and serious adverse events (AEs), hematological and biochemical laboratory parameters were assessed. Mtb72F-specific humoral responses were assessed by ELISA and cell-mediated immune (CMI) responses by intracellular cytokine staining (ICS) and short-term ELISPOT assays. CMI responses to the component peptides (Mtb39a and the Mtb32a C- and N-terminal antigen domains, Mtb32C and Mtb32N) were also assessed by ICS. The Mtb72F/AS02A vaccine appeared to be mainly locally reactogenic but this was considered acceptable, since these AEs were usually transient and resolved within 1-2 days. Most AEs reported were mild in intensity, no serious AEs occurred, no medically significant biochemical or hematological abnormalities related to vaccination were measured and all AEs resolved without sequelae. The vaccine induced statistically significant changes in humoral and CMI response measures. The Mtb72F antigen induced good production of IL-2 and IFNgamma in the ELISPOT assay and CD4(+) T cells expressing at least two activation markers (mainly CD40-L and IL-2) were observed with ICS. A similar CMI profile was observed with Mtb39a and Mtb32N. The induced CMI responses persisted for at least 6 months post-vaccination. All subjects were seropositive for anti-Mtb72F antibodies one month post-dose 2 and 6 months post-dose 3. This first trial in humans found Mtb72F/AS02A to have an acceptable tolerability, to be immunogenic in healthy adults and warrants further development of the vaccine.

Potential adjuvantic properties of innate immune stimuli.

Abstract: Toll-like receptors (TLRs) are a family of conserved pattern recognition receptors (PRRs) that recognize pathogen associated molecular patterns and serve as primary sensors of the innate immune system. Ten members of the TLR family have so far been identified in the human genome. The ligands for these receptors are structurally highly conserved microbial molecules such as lipopolysaccharides (LPS) (recognized by TLR4), lipopeptides (TLR2 in combination with TLR1 or TLR6), flagellin (TLR5), single stranded RNA (TLR7 and TLR8), double-stranded RNA (TLR3), CpG motif-containing DNA (TLR9) and profilin present on uropathogenic bacteria (TLR 11). Complementing the TLRs are the nucleotide-binding domain (NOD), leucine rich repeat containing family (or Nod-like Receptors, NLRs), which detect muramylpeptides released from bacterial peptidoglycan (PGN) in the intracytoplasmic compartment, as well as the retinoic-acid-inducible protein 1 (RIG-I-like receptors; RLRs) which sense single-stranded RNA of viral origin. The activation of PRRs by their cognate ligands leads to production of inflammatory cytokines, upregulation of MHC molecules and co-stimulatory signals in antigen-presenting cells as well as activating natural killer cells, in addition to priming and amplifying antigen-specific T-, and B-cell effector functions. Thus, these stimuli serve to link innate and adaptive immunity and can therefore be exploited as powerful adjuvants in eliciting both primary and anamnestic immune responses. This review summarizes what is currently known about the immunopotentiatory and adjuvantic activities of innate immune stimuli.

Lactococcus lactis as a live vector for mucosal delivery of therapeutic proteins.

Abstract: Food-grade lactic acid bacteria (LAB) have been safely consumed by humans for centuries in fermented foods. Lactococcus lactis, a LAB widely used in the dairy industry as a starter, can be genetically engineered to efficiently produce a large variety of proteins. This feature has been recently exploited by scientists for the development of a new generation of vectors to deliver therapeutic proteins to the mucosal tissues. The successful Phase I clinical trial with a L. lactis strain secreting interleukin-10 for Crohn's disease has opened new horizons for the use of genetically engineered LAB as delivery vehicles. This commentary reviews the current advances made with L. lactis as live vector for the mucosal delivery of therapeutic proteins.

Characterization of the freeze sensitivity of a hepatitis B vaccine

Abstract: Recent studies have revealed that vaccines containing aluminum adjuvant are exposed to sub-zero temperatures while in the cold chain more frequently than was previously believed. This raises concerns that these freeze-sensitive vaccines may be damaged and offer inadequate protection. This study was undertaken to characterize the immediate qualitative changes of one such vaccine, hepatitis B, caused by freeze exposure. Hepatitis B vaccine was subjected to freezing temperatures ranging from 0 degrees C to -20 degrees C for up to three episodes with durations ranging from 1 hour to 7 days. The vaccine was analyzed for freezing point, particle size distribution, tertiary structure, and in vitro and in vivo potency. Whether or not hepatitis B vaccine freezes was shown to be dependent on an array of factors including temperature, rate of temperature change, duration of exposure, supercooling effects and vibration. Vaccine exposed to "mild" freezing (-4 degrees C or warmer) temperatures did not freeze and remained qualitatively unaltered. Single or repeated freezing events at temperatures of -10 degrees C or lower were associated with aggregation of the adjuvant-antigen particles, structural damage of the antigen, and reduction of immunogenicity in mice. Damage to the vaccine increased with duration of freezing, lower temperature, and the number of freezing episodes. With vibration, vaccine froze at -6 degrees C after 1 hour and damage occurred. Freezing and freeze damage to vaccines containing aluminum salt adjuvant represent real risks to the effectiveness of immunization and should be prevented by strengthening the cold chain system or, alternatively, development of freeze-stable vaccine formulations.

Safety of Tdap-IPV given one month after Td-IPV booster in healthy young adults: a placebo-controlled trial.

Abstract: Background: In France, the only vaccines available for use as a pertussis booster in adults are combined vaccines containing adsorbed tetanus, diphtheria (adult formulation), acellular pertussis and inactivated poliovirus (Tdap-IPV). Adults may require a pertussis booster relatively soon after having received vaccines containing tetanus-diptheria antigens (Td)(occupational or familial circumstances as new job, childbirth in recent past or future), although the safety of Tdap-IPV when administered soon after vaccination with Td is undocumented.Methods: In this randomized, double-blind, multi-centre study, we assessed the safety of Tdap-IPV administered 1 month after vaccination with tetanus, diphtheria (adult formulation), inactivated poliovirus vaccination (Td-IPV) in healthy adults vaccinated according to the French vaccination calendar (seven tetanus-diphtheria vaccinations by age 18 years). Subjects received either Td-IPV (n = 249) or placebo (n = 251) followed 1 month later by Tdap-IPV. Any adverse ev...

Sex differences in injection site reactions with human vaccines.

Abstract: Adverse events following immunization (AEFI) are not uncommon, with injection site reactions (ISRs) being the most common. Predictors of injection site reactions are vaccine factors (antigen characteristics, antigen dose, dose number of antigen, antigen adjuvanting and type of diluent), vaccine administration factors (site and route of administration) and vaccinee factors (age and sex, the latter the subject of this review). 1,074 studies which reported ISRs were retrieved by searching of on line journals and databases. Analysis of these data for sex-difference was only reported in 57 studies, with 54 of these studies reporting a sex-difference (42 in subjects >17 years and 12 in subjects <17 years). In accord with the well documented greater pain sensitivity in females compared with males, in all studies with vaccines which reported pain during and post vaccination [hepatitis A, B, diphtheria/tetanus toxoid, diphtheria/tetanus/pertussis(DTaP and Tdap), anthrax and inactivated influenza], females reported a greater rate of pain than males. The pathophysiology of the sex-difference in local reactions (induration, tenderness, erythema, pruritus) following vaccination is clearly multifactorial with hypersensitivity reaction (type III, Arthus reaction-antigen/antibody immune complex formation), route of administration and hormonal factors being suggested. The data presented in this review demonstrate that studies of AEFI should recruit similar numbers of females and males and that these data should be analyzed for sex-difference. Additionally, unlike as at present, reporting of analysis of AEFI data by sex should become standard practice.

Immunogenicity, reactogenicity and safety of human rotavirus vaccine (RIX4414) in Indian infants.

Abstract: Aim: This study was undertaken to assess the immunogenicity, reactogenicity and safety of two doses of an oral live-attenuated human rotavirus vaccine, strain RIX4414 (Rotarix™) in an Indian setting.Patients and Methods: Healthy infants (N=363), approximately 8 weeks of age were enrolled to receive two doses of RIX4414 vaccine (n=182) or placebo (n=181) separated by one month. To assess the immune response, blood samples were taken before vaccination and one month post-dose 2 of RIX4414/placebo. Solicited symptoms were collected for 8-days post each dose and safety data was collected throughout the study.Results: The seroconversion rate observed one month post-dose 2 in the RIX4414 group 58.3% [95% CI: 48.7; 67.4] was significantly higher when compared to the placebo group 6.3%; [95% CI: 2.5; 12.5]. The reactogenicity and safety profile was similar for both groups.Conclusions: Two doses of RIX4414 (Rotarix™) were immunogenic, had a good safety profile and were well-tolerated when administered to healthy I...

Rotavirus vaccines: opportunities and challenges.

Abstract: Each year rotavirus gastroenteritis episodes in young children cause more than 500,000 deaths and 2.4 million hospital admissions worldwide. Vaccine development became a priority when improved personal hygiene and living standards failed to significantly reduce this disease burden. Rotavirus vaccines were developed mimicking natural immunity by protecting against severe gastroenteritis in young children, which would otherwise lead to health-care attendance, hospitalisation or even death. Licensed rotavirus vaccines appear safe and are well-tolerated. In high and middle-income countries they provide 80-100% protection against severe disease and 70-80% protection against rotavirus gastroenteritis of any severity, depending upon the population studied. However, rotavirus vaccines remain to be fully evaluated in low-income countries where reduced immunogenicity of oral vaccines, greater strain diversity and difficulties reaching target populations might decrease immunisation programme performance. Nevertheles...

Improving pertussis vaccination.

Abstract: Despite a high vaccine coverage, pertussis has re-emerged and has become the most prevalent vaccine preventable disease in developed countries. The re-emergence of pertussis has been attributed to various factors, including increased awareness, improved diagnostics, suboptimal vaccines, waning vaccine-induced immunity and pathogen adaptation. Waning immunity in combination with pathogen adaptation are probably the main factors which contribute to the continued circulation of B. pertussis strains. The switch from whole cell vaccines (Pw) to acellular vaccines (Pa) has been successful in reducing side-effects and restoring the public confidence in pertussis immunizations. It has also facilitated the introduction of booster vaccinations at later ages with favorable effects. However, there is still significant circulation of B. pertussis among adolescents and adults who are a major source of infection of infants to young to be (fully) vaccinated. In the short term, the introduction of cocooning vaccination is...

Botulinum neurotoxin vaccines: Past history and recent developments.

Abstract: Botulinum toxin may cause a neuroparalytic illness that may result in respiratory failure and require prolonged mechanical ventilation. As medical resources needed for supportive care of botulism in a bioterrorist event may quickly overwhelm the local healthcare systems, biodefense research efforts have been directed towards the development of a vaccine to prevent botulism. While human botulism has been caused only by toxin serotypes A, B, and E (rarely serotype F), all seven known immunologically distinct toxin serotypes (A - G) may potentially cause intoxication in humans from a bioterrorist event. A pentavalent (ABCDE) botulinum toxoid (PBT) has been administered as an investigation new drug (IND) to at-risk individuals for nearly 50 years. Due to declining immunogenicity of the PBT, research efforts have been directed at development of both improved (less local reactogenicity) botulinum toxoids and recombinant vaccines as potential vaccine candidates to replace the PBT.

Vaccines against nicotine.

Abstract: Medications against any dependence-inducing drug face a dilemma: if they are efficient, they will induce withdrawal symptoms and the patient is likely to stop taking his medication. Anti drug vaccines are irreversible, provide protection over years and need booster injections far beyond the critical phase of acute withdrawal symptoms. Interacting rather with the drug in the blood than with a receptor in the brain, the vaccines are, in addition, free of side effects due to central interaction. For drugs like nicotine interacting with different types of receptors in many organs, this is a further advantage. There are three reasons that anti drug vaccines have first been developed against nicotine. Firstly, in most parts of the world 20 to 50% of the adult population smoke and any smoking cessation treatment will have an important impact on public health and be commercially a very attractive product. The second reason are the smokers themselves, who would like to quit in significant numbers and who have shown good compliance for any form of treatment. Thirdly, the quantities of cocaine or heroine taken by dependant persons are higher than the quantity of nicotine per cigarette, which makes an anti nicotine vaccine the easier vaccine project. Three anti nicotine vaccines are today in an advanced stage of clinical evaluation. We report here how those vaccines work, on the progress of the trials and future developments to expect. Results show that the efficiency of the vaccines is directly related to the antibody levels of the probates, a fact which will help to optimize further the vaccine effect. We expect the vaccines to appear on the market during a time window between 2009 and 2011.

Vaccines and vaccination strategies against human cutaneous leishmaniasis.

Abstract: One might think that the development of a vaccine against cutaneous leishmaniasis would be relatively straightforward because the type of immune response required for protection is known and natural immunity occurs following recovery from primary infection. However, there is as yet no effective vaccine against the disease in humans. Although vaccination in murine studies has yielded promising results, these vaccines have failed miserably when tested in primates or humans. The reasons behind these failures are unknown and remain a major hurdle for vaccine design and development against cutaneous leishmaniasis. In contrast, recovery from natural, deliberate or experimental infections results in development of long-lasting immunity to re-infection. This so called infection-induced resistance is the strongest anti-Leishmania immunity known. Here, we briefly review the different approaches to vaccination against cutaneous leishmaniasis and argue that vaccines composed of genetically modified (attenuated) parasites, which induce immunity akin to infection-induced resistance, may provide best protection against cutaneous leishmaniasis in humans.

Attenuated poxvirus vectors MVA and NYVAC as promising vaccine cadidates against HIV/AIDS

Abstract: As yet, the only human infectious disease eradicated from our planet is smallpox, caused by variola virus a member of the poxvirus family. The vaccination success, with the declaration by WHO in 1980 of a worldwide free of smallpox, was largely due to the availability of a quite effective and stable live vaccine, as well as the restricted human host for virus infection. Variola was considered one of the most devastating diseases of human mankind. With the sudden appearance of the HIV/AIDS in 1981, an infection which spread rapidly to become a pandemic in a short time, causing up to date more than 22 million deaths, about 40 million people infected and a current incidence of about 3 million deaths per year, this dreadful pandemic has become one of the most severe diseases in the World, specially in poor countries. While different antiviral drugs have been developed that block virus replication at various stages of infection, however the rapid virus escape that follows during the drug therapy due to mutatio...

The green vaccine: A global strategy to combat infectious and autoimmune diseases.

Abstract: Plant derived oral green vaccines eliminate expenses associated with fermenters, purification, cold storage/transportation and sterile delivery. Green vaccines are expressed via the plant nuclear or chloroplast genomes. Chloroplast expression has advantages of hyper-expression of therapeutic proteins (10,000 copies of trans-gene per cell), efficient oral delivery and transgene containment via maternal inheritance. To date, 23 vaccine antigens against 16 different bacterial, viral or protozoan pathogens have been expressed in chloroplasts. Mice subcutaneously immunized with the chloroplast derived anthrax protective antigen conferred 100% protection against lethal doses of the anthrax toxin. Oral immunization (ORV) of F1-V antigens without adjuvant conferred greater protection (88%) against 50-fold lethal dose of aerosolized plague (Yersinia pestis) than subcutaneous (SQV) immunization (33%). Oral immunization of malarial vaccine antigens fused to the cholera antigen (CTB-AMA1/CTB-Msp1) conferred prolonged immunity (50% life span), 100% protection against cholera toxin challenge and inhibited proliferation of the malarial parasite. Protection was correlated with antigen-specific titers of intestinal, serum IgA & IgG1 in ORV and only IgG1 in SQV mice, but no other immunoglobulin. High level expression in edible plant chloroplasts ideal for oral delivery and long-term immunity observed should facilitate development of low cost human vaccines for large populations, at times of outbreak.

Seropersistence of tick-borne encephalitis antibodies, safety and booster response to FSME-IMMUN 0.5 ml in adults aged 18-67 years.

Abstract: A clinical study was carried out to evaluate the persistence of tick-borne encephalitis (TBE) antibodies 2 and 3 years after a primary vaccination series (three-dose regimen), and to assess the antibody response to a booster vaccination with FSME-IMMUN. Volunteers (N = 347, 18-67 years) who had received two doses of either FSME-IMMUN or Encepur adults and a third vaccination with FSME-IMMUN were enrolled. Seropositivity rates were assessed by ELISA and neutralization test (NT). After the primary series, seropositivity rates were 99.1% as determined by ELISA and 100% by NT, decreasing to 85% and 96.8% in the first two years and to 88.7% and 95.4% after 3 years. Following booster vaccination, 100% of subjects were seropositive. Age was the only variable with a significant influence on the probability of remaining TBE seropositive 2 or 3 years after the third vaccination. In subjects aged 18-50 years, the pre-booster seropositivity rate was higher (88.7% and 92.3% after 2 and 3 years, respectively) than in those aged 51-67 years (65.5% and 70.9% after 2 and 3 years, respectively). Adverse events after booster vaccination occurred with a low frequency and were predominantly mild. An annual TBE antibody decline rate of 0.58 (based on NT) was estimated to lead to antibody titer decrease from e.g., 260 to 45.6 after 3 years. To conclude, a booster vaccination with FSME-IMMUN, administered 3 years after primary vaccination, is well tolerated and induces a

Challenges in developing a pediatric RSV vaccine.

Abstract: RSV bronchiolitis is the leading cause of infant hospitalization in industrialized countries. There is an unmet need to prevent RSV lower respiratory tract infection in young infants. Although many vaccinology approaches, including live attenuated, viral and bacterial vectored and adjuvanted subunit vaccines have been evaluated in rodent and primate models there is currently no approved RSV vaccine. A vaccine candidate for RSV-naive infants must provide immunogenicity in the presence of maternally acquired antibodies, avoid enhanced disease and have minimal reactogenicity. Because live RSV infection does not potentiate for enhanced disease and elicits systemic and mucosal immune responses, live RSV vaccine candidates are currently preferred. Two live attenuated RSV vaccine candidates, rA2cpts248/404/1030/DeltaSH, a temperature sensitive RSV with a deletion of the SH gene, and rb/h PIV3/RSV F2 which has RSV F vectored into a bovine/human chimeric parainfluenza type 3 genome, have recently advanced into clinical studies.

Vaccination strategies and vaccine formulations for epidemic and pandemic influenza control.

Abstract: Influenza viruses of the H5N1 subtype cause an ever-increasing number of bird-to-human transmissions and a pandemic outbreak caused by these viruses is imminent. Therefore, the availability of safe and effective vaccines is highly desirable and their development considered a priority. However, using production and use of seasonal influenza vaccine as template for the production of pandemic H5N1 vaccines did not yield effective vaccines. High antigen doses were required to induce appreciable antibody responses. In addition, limited production capacity and long production times are other disadvantages of conventional influenza vaccine preparations. Here, we review recent developments that will contribute to a more rapid availability of sufficient doses of highly efficacious and safe pandemic influenza vaccines. The new developments include the establishment of novel methods to prepare vaccine strains, novel production technologies and the use of novel adjuvants and alternative vaccine formulations.

Vaccines against morphine/heroin and its use as effective medication for preventing relapse to opiate addictive behaviors.

Abstract: Current pharmacotherapies for treating morphine/heroin dependence are designed to substitute or block addiction by targeting the drug itself rather than the brain. Heroin addict is still being exposed to addictive opiates, and consequently may develop tolerance to and experience withdrawal and drug´s toxic effects from the treatment with high incidence of relapse to addictive drug consumption. As for other drugs of abuse, an alternative approach for morphine/heroin addiction is an antibody-based antagonism of heroin´s brain entry. This review summarizes the literature examining important aspects of neurobiological and pharmacological processes involved in opiate dependence. Thereafter, classical pharmacological interventions for opiate dependence treatment and its major clinical limitations are reviewed. Finally, relevant preclinical studies are examined for comparisons in the design, use, immunogenic profile and efficacy of several models of morphine/heroin vaccine as immunologic interventions on th...

Development of active and passive human vaccines to treat methamphetamine addiction.

Abstract: Methamphetamine (METH) abuse is a major worldwide epidemic, with no specific medications for treatment of chronic or acute effects. Anti-METH antibodies have the potential to save lives and reduce the crippling effects of METH abuse. While they are not expected to be the magic bullet to immediately cure addiction, immunotherapy could provide a breakthrough medication to continuously block or attenuate METH effects during a comprehensive addiction recovery plan. A unique challenge for METH antibody antagonists is the need to protect the brain from the complex direct and indirect adverse effects of long-term METH use. To meet this challenge, a new generation of passive monoclonal antibodies and active immunization therapies are at an advanced stage of preclinical development. Both of these vaccines could play an essential role in a well planned recovery program from human METH addiction by providing long-lasting protection from the rewarding and reinforcing effect of METH.

Antibodies to tetanus, diphtheria and pertussis among healthy adults vaccinated according to the French vaccination recommendations

Abstract: In this sero-epidemiological study, we investigated humoral immunity to three vaccine-preventable diseases—tetanus, diphtheria and pertussis—among 331 adults (aged 18–60 years) attending vaccination centres for travellers and who had been vaccinated according to national recommendations in France. Serological results showed that the percentage of subjects with antibodies to diphtheria and tetanus decreases with age. Results also confirmed surveillance data on vaccination in France, with 7.6% of the study population (13.4% of those aged 18–29 years) having recently acquired a pertussis infection. These results confirm the importance of following French recommendations for regular boosters for tetanus and diphtheria among adults. They also indicate the need for better implementation of the current recommendations for pertussis-vaccine boosters in adults.

Attitudes to HPV vaccination among ethnic minority mothers in the UK: An exploratory qualitative study

Abstract: Objective: The objective of this study was to explore attitudes to HPV vaccination among Black and Asian mothers living in Britain.Design: This study used qualitative methodology. Face-to-face interviews were carried out with Black/Black British (n = 10) and Asian/Asian British mothers (n = 10). Interviews lasted approximately 40 minutes, were recorded and transcribed verbatim. Data were analysed using Framework Analysis.Results: Five major themes emerged from the data: i) Experience of vaccination, ii) Awareness of HPV vaccination and reactions to the information, iii) reasons for giving vaccination, iv) concerns about vaccination and v) social influences. Visits to family abroad meant additional experience with vaccinations. There were concerns about how vaccine effects could vary by ethnicity as a result of physical differences (e.g. sickle-cell anaemia), and mothers wanted to know whether the HPV vaccine had been tested fully in their ethnic group. Most mothers struggled to understand why their da...

Cervarix, the GSK HPV-16/HPV-18 AS04-adjuvanted cervical cancer vaccine, demonstrates stability upon long-term storage and under simulated cold chain break conditions.

Abstract: Cervarix is a recombinant human papillomavirus (HPV)-16 and -18 L1 virus-like-particle (VLP) AS04-adjuvanted vaccine designed to protect against cervical intraepithelial neoplasia and cervical cancer caused by the HPV types 16 and 18 Assessment of the stability of the vaccine during long-term storage and after transient exposure to temperatures out of normal storage range is an integrated part of vaccine quality evaluation This assessment was done with vaccine samples stored at 2-8 degrees C for up to 36 months, with or without simulated cold chain break (either one week at 37 degrees C, or two or four weeks at 25 degrees C) Among the stability-indicating parameters, antigenicity and immunogenicity were evaluated along with L1 antigen integrity and adsorption to aluminum Differential scanning calorimetry (DSC) was used to investigate the structural stability of the VLPs before and after vaccine formulation and over time Cervarix was stable at 2-8 degrees C for at least three years, and the occurrence of cold chain break had no impact, as shown by unchanged product characteristics during the full storage period DSC analysis demonstrated that the structure of the HPV-16 and -18 L1 proteins and their corresponding VLPs was not affected throughout the manufacturing process Moreover, the structure of aluminum-adsorbed HPV-16 and -18 L1 VLPs was robust over a 14-month test period In conclusion, Cervarix was very stable upon long-term storage at 2-8 degrees C with or without transient exposure to higher temperatures (up to 37 degrees C) The observed robust structure of the L1 VLPs contributes to the excellent stability of Cervarix

Vaccines for cocaine abuse.

Abstract: Treatments for cocaine abuse have been disappointingly ineffective, especially in comparison with those for some other abused substances. A new approach, using vaccination to elicit specific antibodies to block the access of cocaine to the brain, has shown considerable promise in animal models, and more recently in human trials. The mechanism of action for the antibody effect on cocaine is very likely to be the straightforward and intuitive result of the binding of the drug in circulation by antibodies, thereby reducing its entry into the central nervous system and thus its pharmacological effects. The effectiveness of such antibodies on drug pharmacodynamics is a function of both the quantitative and the qualitative properties of the antibodies, and this combination will determine the success of the clinical applications of anti-cocaine vaccines in helping addicts discontinue cocaine abuse. This review will discuss these issues and present the current developmental status of cocaine conjugate vaccines.

Immune memory to hepatitis B virus in 4-to-9-year old children vaccinated in infancy with four doses of hexavalent DTPa-HBV-IPV/Hib vaccine

Abstract: The combined hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio Haemophilus influenzae type b (DTPa-HBV-IPV/Hib) vaccine produces similar hepatitis B responses as the HBV monovalent vaccine. Booster vaccination of immunocompetent individuals primed against hepatitis B in infancy is currently not recommended. We investigated persisting immunity to hepatitis B in 4-6 (Study A; 106745) and 7-9 (Study B; 106744) year-old children primed in infancy and boosted in the second year of life with DTPa-HBV-IPV/Hib. Immunity was assessed by measuring persisting anti-HBs antibodies and evaluating the response to a challenge dose of HBV vaccine. At 4-6 years of age 86.0% of 186 subjects had persisting anti-HBs ≥10mIU/ml increasing to 98.4% after the challenge. At 7-9 years of age, 78.0% of 186 subjects continued to have anti-HBs antibody concentrations ≥10mIU/ml, increasing to 98.9% after the challenge. In both studies anti-HBs antibody GMC rose >80-fold. An anamnestic response to the HBV c...