Non-clinical efficacy and safety of HyVac4:IC31 vaccine administered in a BCG prime–boost regimen

Despite the extensive success with the introduction of M. bovis Bacille Calmette-Guérin (BCG), tuberculosis (TB) remains a major global epidemic infecting between 8 and 9 million people annually with an estimated 1.7 million deaths each year. However, because of its demonstrated effectiveness against some of the most severe forms of childhood TB, it is now realized that BCG vaccination of newborns is unlikely to be replaced. Therefore, BCG or an improved BCG will continue to be used as a prime TB vaccine and there is a need to develop effective boost vaccines that would enhance and prolong the protective immunity induced by BCG prime immunization. We report on a heterologous booster approach using two highly immunogenic TB antigens comprising Ag85B and TB10.4 (HyVac4) delivered as a fusion molecule and formulated in the proprietary adjuvant IC31. This vaccine was found to be immunogenic and demonstrated greater protection in the more stringent guinea pig model of pulmonary tuberculosis than BCG alone when used in a prime/boost regimen. Significant difference in lung involvement was observed for all animals in the HyVac4 boosted group compared to BCG alone regardless of time to death or sacrifice. A vaccine toxicology study of the HyVac4:IC31 regimen was performed and it was judged safe to advance the vaccine into clinical trials. Therefore, all non-clinical data supports the suitability of HyVac4 as a safe, immunogenic, and effective vaccination in a prime–boost regimen with BCG.     

Safety and immunogenicity of pneumococcal protein vaccine candidates: Monovalent choline-binding protein A (PcpA) vaccine and bivalent PcpA–pneumococcal histidine triad protein D vaccine

Background

Pneumococcal vaccines based on protein antigens may provide expanded protection against Streptococcus pneumoniae.

Objective

To evaluate safety and immunogenicity in adults of pneumococcal vaccine candidates comprising S. pneumoniae pneumococcal histidine triad protein D (PhtD) and pneumococcal choline-binding protein A (PcpA) in monovalent and bivalent formulations.

Methods

This was a phase I, randomized, observer-blinded, placebo-controlled, step-wise dose-escalation study. Following a pilot safety study in which participants received one intramuscular injection of either aluminum hydroxide (AH)–adjuvanted PcpA (25 μg) or PhtD–PcpA (10 μg each), participants in the main study received AH–adjuvanted PcpA (25 μg), AH–adjuvanted PhtD–PcpA (10, 25, or 50 μg each), unadjuvanted PhtD–PcpA (25 μg each), or placebo as 2 injections 30 days apart. Assignment of successive dose cohorts was made after blinded safety reviews after each dose level. Safety endpoints included rates of solicited injection site and systemic reactions, unsolicited adverse events (AEs), serious AEs (SAEs), and safety laboratory tests. Immunogenicity endpoints included levels of anti-PhtD and anti-PcpA antibodies (ELISA).

Results

Six adults 18–50 years of age were included in the pilot study and 125 in the main study. No obvious increases in solicited reactions or unsolicited AEs were reported with escalating doses (adjuvanted vaccine) after either injection, or with repeated administration. Adjuvanted vaccine candidates were associated with a higher incidence of solicited reactions (particularly injection site reactions) than unadjuvanted vaccine candidates. However, no SAE or discontinuation due to an AE occurred. Geometric mean concentrations of anti-PhtD IgG and anti-PcpA IgG increased significantly after injection 2 compared with injection 1 at each dose level. No enhancement of immune responses was shown with adjuvanted vaccine candidates compared with the unadjuvanted vaccine candidate. In the dose-escalating comparison, a plateau effect at the 25 μg dose was observed as measured by geometric mean concentrations and by fold increases.

Conclusions

Promising safety profiles and immunogenicity of these monovalent and bivalent protein vaccine candidates were demonstrated in an adult population (ClinicalTrials.gov registry no. NCT01444339).     

Enhanced immune responses to E2 protein and DNA formulated with ISA 61 VG administered as a DNA prime–protein boost regimen against bovine viral diarrhea virus

The aim of this study was to develop and test an optimal vaccination strategy against bovine viral diarrhea virus (BVDV) based on the E2 glycoprotein of the BJ1305 strain. To achieve higher E2-specific antibody titers and to broaden the cellular immune response, a plasmid encoding the E2 protein (pcDNA3.1-E2) was constructed and a purified recombinant E2 protein was generated. The E2 protein was emulsified in the adjuvant ISA 61 VG prior to administration. We immunized mice three times with pcDNA3.1-E2 or the recombinant E2 protein or primed twice with pcDNA3.1-E2 and boosted once with the E2 protein. To evaluate the protection against BVDV conferred by the vaccines, the mice were challenged with BVDV strain Oregon C24V after the third immunization. Although all immunized mice developed humoral and cellular immune responses, the E2-specific antibody titers in the DNA prime–protein boost group were significantly higher than those elicited by either the DNA or the protein vaccine. In addition, vaccination with the E2 DNA vaccine induced higher percentages of CD4⁺IFN-γ⁺ T cells and CD8⁺IFN-γ⁺ T cells among total CD3⁺ T cells than the other regimens. The predominant antibody subclass in the vaccinated mice was IgG1. Serum tumor necrosis factor alpha (TNF-α) levels in the DNA prime–protein boost group were significantly higher after the third immunization than in the other groups. Moreover, the mice treated with the DNA prime–protein boost vaccination regimen acquired protection against BVDV challenge, as shown by a significant reduction of viremia, only minor pathological changes, and a lower viral antigen burden than in the control and solo vaccinated mice. These results demonstrate the potential advantage of a DNA prime–protein boost vaccination approach over a solo vaccination for the prevention of BVDV. The ability of this vaccine strategy to control and eradicate BVD in herds warrants further investigation.     

A recombinant DNA and vaccinia virus prime–boost regimen induces potent long-term T-cell responses to HCV in BALB/c mice

To explore the best prime–boost regimen and evaluate the T-cellular response memory against HCV, we constructed two DNA vaccine candidates (pVRC-CE1E2 and pAAV-CE1E2) and two recombinant viruses (rTTV-E1E2 and rAAV-E1E2) and then assessed the immune response to different prime–boost patterns in BALB/c mice. The rTTV-E1E2 boosted the immune response to HCV DNA vaccine prime significantly, and the inverted terminal repeat sequence harboring DNA construct PAAV-CE1E2 was the best prime agent in this study. Our study provides new information for both the prime–boost regimen and long-term T-cell response for HCV vaccine development.     

Autophagy-targeted vaccine of LC3–LpqH DNA and its protective immunity in a murine model of tuberculosis

The development of more effective antituberculosis vaccines would contribute to the control of the global problem of infection with Mycobacterium tuberculosis (MTB). Recently, the highlighted importance of autophagy in the host immune response against MTB has attracted the attention of researchers. However, the vaccines targeted at autophagy remain to be developed. In this study, we report on an autophagy-targeted vaccine of 19 kDa MTB lipoprotein (LpqH) DNA that harbors another gene coding microtubule-associated protein light chain-3(LC3), which transports LpqH to autophagosomes and displays enhanced protective efficacy against MTB. After the transfection of pCMV-LpqH DNA, a significant increase LC3 II was detected in RAW264.7 cells, which was similar to that observed with treatment with rapamycin, a reagent used to induce autophagy. To target autophagy, the gene coding LC3, as a marked protein of autophagosome, was linked to the lpqH gene to express an LC3–LpqH fused protein. Interestingly, LC3–LpqH fused protein was determined to be transported to an autophagosome, which was demonstrated by the co-localization of GFP-LC3 with LC3–LpqH at autophagosomes. Notably, the mice immunized with LC3–LpqH/Ag85B displayed decreased mycobacterial loads in the lungs and spleen when challenged with virulent MTB by intravenous infection, which was consistent with increased IgG2a in serum and IFN-γ and IL-2 produced by splenocyte. In conclusion, our study demonstrates that an LC3–LpqH DNA vaccine could have autophagy as its target, which contributes to the enhancement of the Th1 immune response and vaccine protective efficacy.     

Pulmonary delivery of DNA encoding Mycobacterium tuberculosis latency antigen Rv1733c associated to PLGA–PEI nanoparticles enhances T cell responses in a DNA prime/protein boost vaccination regimen in mice

During persistent infection and hypoxic-stress, Mycobacterium tuberculosis (Mtb) expresses a series of Mtb latency antigens. The aim of this study was to evaluate the immunogenicity of a DNA vaccine encoding the Mtb latency antigen Rv1733c and to explore the effect of pulmonary delivery and co-formulation with poly (d,l-lactide-co-glycolide) (PLGA)–polyethyleneimine (PEI) nanoparticles (np) on host immunity. Characterization studies indicated that PLGA–PEI np kept their nanometer size after concentration and were positively charged. The np were able to mature human dendritic cells and stimulated them to secrete IL-12 and TNF-α comparable to levels observed after lipopolysaccharide (LPS) stimulation. Mtb latency antigen Rv1733c DNA prime combined with Rv1733c protein boost enhanced T cell proliferation and IFN-γ secretion in mice in response to Rv1733c and Mtb hypoxic lysate. Rv1733c DNA adsorbed to PLGA–PEI np and applied to the lungs increased T cell proliferation and IFN-γ production more potently compared to the same vaccinations given intramuscularly. The strongest immunogenicity was obtained by pulmonary priming with np-adsorbed Rv1733c DNA followed by boosting with Rv1733c protein. These results confirm that PLGA–PEI np are an efficient DNA vaccine delivery system to enhance T cell responses through pulmonary delivery in a DNA prime/protein boost vaccine regimen.     

Long-term (5-year) antibody persistence following two- and three-dose regimens of a combined hepatitis A and B vaccine in children aged 1–11 years

This study compared the long-term persistence of anti-hepatitis A (anti-HAV) and B (anti-HBs) antibodies, 5 years after vaccination of subjects aged 1–11 years with a combined hepatitis A and B vaccine either in a two-dose (0, 6 months, Adult formulation) or a three-dose (0, 1, 6 months, Paediatric formulation) schedule. At the end of the 5 years, all subjects (100%) in both groups continued to have anti-HAV antibodies ≥15 mIU/mL, while 94–97% of subjects in both groups had anti-HBs antibody concentrations ≥10 mIU/mL. Subjects with anti-HBs antibody concentration ≤10 mIU/mL were administered a challenge dose of hepatitis B vaccine. All subjects mounted a vigorous immune response to the challenge indicating the presence of immunological memory to HBV.     

Immunogenicity and safety of an investigational hepatitis B vaccine with a Toll-like receptor 9 agonist adjuvant (HBsAg-1018) compared to a licensed hepatitis B vaccine in healthy adults 40–70 years of age

Background

The currently licensed hepatitis B vaccines have limitations including hyporesponsiveness in older adults, poor compliance, and the extended time for most persons to develop seroprotection (e.g. >6 months). A vaccine containing HBsAg combined with a Toll-like receptor 9 agonist adjuvant (HBsAg-1018) has been developed to overcome these limitations.

Methods

A Phase 3, multicenter, randomized, subject- and observer-blinded, active-controlled trial was conducted among healthy subjects 40–70 years of age comparing the immunogenicity and safety of two doses of HBsAg-1018 at 0 and 4 weeks to three doses of licensed hepatitis B vaccine, HBsAg-Eng, at 0, 4, and 24 weeks. The primary immunogenicity endpoint was noninferiority of the seroprotection rate (SPR; % with anti-HBs ≥10 mIU/mL) of HBsAg-1018 compared to the SPR of HBsAg-Eng at 8 weeks following the last dose of vaccine. Conditional upon meeting noninferiority, superiority of HBsAg-1018 over HBsAg-Eng was assessed. Safety was compared between the two vaccines.

Results

At the primary endpoint, the SPR for the HBsAg-1018 group (90.0%) was superior to the SPR for the HBsAg-Eng group (70.5%) with an SPR difference of 19.5% (95% CI, 14.7%, 24.7%). At week 28 when the SPR peaked in the HBsAg-Eng group (72.8%), the SPR in the HBsAg-1018 group (94.8%) was significantly higher than in the HBsAg-Eng group. The SPR in the HBsAg-1018 group was significantly higher than in the HBsAg-Eng group at each study visit from week 4 through week 52. The safety profiles for the two vaccines were similar.

Conclusion

When compared to the HBsAg-Eng three-dose regimen given at 0, 1, and 6 months, HBsAg-1018 demonstrated superior seroprotection with only two doses at 0 and 1 month. The safety profile of HBsAg-1018 was comparable to that of the licensed vaccine, HBsAg-Eng. HBsAg-1018 would provide a significant public health contribution toward the prevention of hepatitis B infection.     

A phase I trial evaluating the safety and immunogenicity of a candidate tuberculosis vaccination regimen,ChAdOx1 85A prime – MVA85A boost in healthy UK adults

BackgroundThis phase I trial evaluated the safety and immunogenicity of a candidate tuberculosis vaccination regimen, ChAdOx1 85A prime-MVA85A boost, previously demonstrated to be protective in animal studies, in healthy UK adults.MethodsWe enrolled 42 healthy, BCG-vaccinated adults into 4 groups: low dose Starter Group (n = 6; ChAdOx1 85A alone), high dose groups; Group A (n = 12; ChAdOx1 85A), Group B (n = 12; ChAdOx1 85A prime – MVA85A boost) or Group C (n = 12; ChAdOx1 85A – ChAdOx1 85A prime – MVA85A boost). Safety was determined by collection of solicited and unsolicited vaccine-related adverse events (AEs). Immunogenicity was measured by antigen-specific ex-vivo IFN-γ ELISpot, IgG serum ELISA, and antigen-specific intracellular IFN-γ, TNF-α, IL-2 and IL-17.ResultsAEs were mostly mild/moderate, with no Serious Adverse Events. ChAdOx1 85A induced Ag85A-specific ELISpot and intracellular cytokine CD4+ and CD8+ T cell responses, which were not boosted by a second dose, but were boosted with MVA85A. Polyfunctional CD4+ T cells (IFN-γ, TNF-α and IL-2) and IFN-γ+, TNF-α+ CD8+ T cells were induced by ChAdOx1 85A and boosted by MVA85A. ChAdOx1 85A induced serum Ag85A IgG responses which were boosted by MVA85A.ConclusionA ChAdOx1 85A prime – MVA85A boost is well tolerated and immunogenic in healthy UK adults.     

Cloning and assessment of tumorigenicity and oncogenicity of a Madin–Darby canine kidney (MDCK) cell line for influenza vaccine production

An Madin–Darby canine kidney (MDCK) cell line, 9B9-1E4, was cloned by limit dilution from a heterologous cell population and chosen as a potential production cell substrate for cell culture-based influenza vaccine manufacture. Since MDCK cells are transformed cells of canine origin, extensive characterization, including evaluation of tumorigenicity and oncogenicity, was performed to ensure the safety of this cell line for vaccine production. Injection of intact MDCK cells into adult and newborn athymic nude mice did not lead to progressive tumor formation in two separate tumorigenicity studies. In addition, neither MDCK cell lysate nor cellular DNA induced tumors in newborn rodents (athymic nude mice, hamsters and rats) in six oncogenicity studies. Observations from these studies demonstrate the low tumorigenic and oncogenic potential of the MDCK cell clone 9B9-1E4. These observations coupled with other characterization study results strongly suggest a high safety assurance level can be achieved through cell cloning and selection of low tumorigenic and oncogenic cells for influenza vaccine production.     

Indicators of therapeutic effect in FIT-06, a Phase II trial of a DNA vaccine, GTU(®)-Multi-HIVB, in untreated HIV-1 infected subjects

Background

Combination highly active antiretroviral therapy (HAART) has significantly decreased HIV-1 related morbidity and mortality globally transforming HIV into a controllable condition. HAART has a number of limitations though, including limited access in resource constrained countries, which have driven the search for simpler, affordable HIV-1 treatment modalities. Therapeutic HIV-1 vaccines aim to provide immunological support to slow disease progression and decrease transmission. We evaluated the safety, immunogenicity and clinical effect of a novel recombinant plasmid DNA therapeutic HIV-1 vaccine, GTU^®-multi-HIVB, containing 6 different genes derived from an HIV-1 subtype B isolate.

Methods

63 untreated, healthy, HIV-1 infected, adults between 18 and 40 years were enrolled in a single-blinded, placebo-controlled Phase II trial in South Africa. Subjects were HIV-1 subtype C infected, had never received antiretrovirals, with CD4 ≥ 350 cells/mm³ and pHIV-RNA ≥ 50 copies/mL at screening. Subjects were allocated to vaccine or placebo groups in a 2:1 ratio either administered intradermally (ID) (0.5 mg/dose) or intramuscularly (IM) (1 mg/dose) at 0, 4 and 12 weeks boosted at 76 and 80 weeks with 1 mg/dose (ID) and 2 mg/dose (IM), respectively. Safety was assessed by adverse event monitoring and immunogenicity by HIV-1-specific CD4+ and CD8+ T-cells using intracellular cytokine staining (ICS), pHIV-RNA and CD4 counts.

Results

Vaccine was safe and well tolerated with no vaccine related serious adverse events. Significant declines in log pHIV-RNA (p = 0.012) and increases in CD4+ T cell counts (p = 0.066) were observed in the vaccine group compared to placebo, more pronounced after IM administration and in some HLA haplotypes (B*5703) maintained for 17 months after the final immunisation.

Conclusions

The GTU^®-multi-HIVB plasmid recombinant DNA therapeutic HIV-1 vaccine is safe, well tolerated and favourably affects pHIV-RNA and CD4 counts in untreated HIV-1infected individuals after IM administration in subjects with HLA B*57, B*8101 and B*5801haplotypes.     

Structure–activity relationship of lipopeptide Group A streptococcus (GAS) vaccine candidates on toll-like receptor 2

Incorporation of lipoamino acids (LAAs) into peptide structures effectively imparts self-adjuvanting activity onto otherwise ineffective immunogens. Our fully synthetic lipopeptide vaccine candidates against group A streptococcus (GAS) were composed of J14 as a target GAS B-cell epitope alongside a universal helper T-cell epitope (P25) and a LAA-based lipid moiety. In the current study, we investigated the ability of our lipopeptides to activate nuclear factor-κB (NF-κB) in a toll-like receptor-2 (TLR2)-dependent manner as the possible mode of action and reported the structure–function requirements for novel TLR2 targeting lipopeptides based on LAAs. The NF-κB activation was dependent on the dose and the length of the alkyl chains of the incorporated lipid moieties with the hierarchy LAA 3 (16 carbons) > LAA 2 (14 carbons) > LAA 1 (12 carbons). The position of the lipid moiety (C-terminus vs. N^?-terminus of the central lysine residue) does not significantly affect NF-κB activation. Lipopeptides containing different copies of LAA 3 were synthesized and the di-lipidated analogue was the most effective in NFκB activation.     

Immunogenicity and reactogenicity of a decennial booster dose of a combined reduced-antigen-content diphtheria–tetanus–acellular pertussis and inactivated poliovirus booster vaccine (dTpa–IPV) in healthy adults

BackgroundPertussis in adults and adolescents could be reduced by replacing traditional tetanus and diphtheria (Td) boosters with reduced-antigen-content diphtheria–tetanus–acellular pertussis (dTpa) vaccines. This study evaluated the administration of dTpa–IPV (dTpa–inactivated poliovirus) in adults ten years after they received a booster dose of either dTpa–IPV, dTpa+IPV or Td–IPV in trial NCT01277705.MethodsOpen multicentre, phase IV study (www.clinicaltrials.gov NCT01323959) in which healthy adults, who had received a previous dose of dTpa–IPV, dTpa+IPV or Td–IPV ten years earlier, received a single decennial booster dose of dTpa–IPV (Boostrix™-polio, GlaxoSmithKline Vaccines). Blood samples were collected before and one month after booster vaccination. Antibody concentrations against all vaccine antigens were measured and reactogenicity and safety were assessed.ResultsA total of 211 subjects (mean age 50.3 years) received vaccination of whom 201 were included in the according-to-protocol cohort for immunogenicity. Before the decennial dTpa–IPV booster, ≥71.0% subjects were seroprotected/seropositive against all vaccine antigens. One month after the booster dose, all subjects were seroprotected against tetanus and poliovirus types 2 and 3; ≥95.7% subjects were seroprotected against diphtheria and ≥98.3% against poliovirus type 1. Anti-pertussis booster responses for the various antigens were observed in ≥76.5% (pertussis toxoid; PT), ≥85.1% (filamentous haemagglutinin; FHA) and ≥63.2% (pertactin; PRN) of subjects. During the 4-day follow-up, the overall incidence of local AEs was 71.6%, 75.0% and 72.2% in dTpa–IPV, dTpa+IPV and Td–IPV groups, respectively. Pain was the most frequent solicited local adverse event (AE; ≥62.7% subjects) and fatigue the most frequent solicited general AE (≥18.5%). No serious AEs were reported during the study.ConclusionA booster dose of dTpa–IPV was immunogenic and well tolerated in adults who had received a booster dose of either dTpa–IPV, dTpa+IPV or Td–IPV, ten years previously and supports the repeated administration of dTpa–IPV.     

Immunogenicity of an investigational hepatitis B vaccine with a toll-like receptor 9 agonist adjuvant (HBsAg-1018) compared with a licensed hepatitis B vaccine in subpopulations of healthy adults 18–70 years of age

BackgroundImmunologic response to a complete vaccine regimen of currently licensed alum-adjuvanted hepatitis B vaccines is reduced in several subpopulations, including older adults, men, obese persons, and smokers. Two phase 3 trials in healthy adults demonstrated that 2 doses over 1 month of an investigational hepatitis B vaccine (HBsAg-1018) induced superior seroprotection rates (SPRs) to 3 doses over 6 months of the licensed vaccine Engerix-B^® (HBsAg-Eng).MethodsAn exploratory analysis of immunogenicity was conducted in subpopulations from pooled data for the 2 phase 3 trials.ResultsIn each subpopulation, the peak SPR in the HBsAg-1018 group was statistically significantly higher than the peak SPR in the HBsAg-Eng group. Peak HBsAg-1018 SPRs ranged from 91.6% to 99.7%, while peak HBsAg-Eng SPRs ranged from 67.7% to 92.9%.ConclusionIn these exploratory analyses, 2 doses of HBsAg-1018 induced statistically significantly higher rates of seroprotection than 3 doses of HBsAg-Eng across all subpopulations.     

A randomized clinical trial to identify the optimal antigen and MF59(®) adjuvant dose of a monovalent A/H1N1 pandemic influenza vaccine in healthy adult and elderly subjects

Background

Vaccines against pandemic A/H1N1 influenza are required to protect the entire population. This dose range study aimed to identify priming antigen and adjuvant doses resulting in optimal levels of antibody-mediated protection after primary and one-year booster immunizations.

Methods

This randomised trial enrolled 410 healthy adult (18–60 years) and 251 healthy elderly (>60 years) participants. Subjects received vaccine containing either 3.75 μg or 7.5 μg antigen, adjuvanted with half the standard dose, or a standard dose of MF59^® (Novartis Vaccines) adjuvant, respectively. An additional adult cohort received non-adjuvanted vaccine containing 15 μg antigen. Two doses of investigational vaccine were administered three weeks apart, followed by a single booster dose of adjuvanted seasonal influenza vaccine one year after priming. Immunogenicity was assessed by haemagglutination inhibition and microneutralization assays pre- and post-immunization, the safety profile of each vaccine was also evaluated.

Results

All of the vaccine formulations investigated were highly immunogenic and well tolerated in both adult and elderly subjects. The 7.5 μg formulation induced the highest antibody titres after primary and booster immunizations, and resulted in better long-term antibody persistence, in both age groups. Assessment according to European licensure criteria for influenza vaccines concluded that single adjuvanted priming doses containing 3.75 μg and 7.5 μg antigen were optimal for the adult and elderly populations, respectively.

Conclusions

These data demonstrate that one priming dose of MF59-adjuvanted A/H1N1 vaccine provided healthy adult (3.75 μg or 7.5 μg formulations) and healthy elderly (7.5 μg formulation) individuals with adequate levels of seroprotection. Booster administration after two priming doses of either vaccine formulation resulted in the rapid development of seroprotective antibody titres.

Trial registration

www.clinicaltrials.gov (NCT00971906).     

Safety and immunogenicity of recombinant Bacille Calmette-Guérin (rBCG) expressing Borrelia burgdorferi outer surface protein A (OspA) lipoprotein in adult volunteers: a candidate Lyme disease vaccine

This phase I clinical trial was designed to determine the feasibility of using rBCG as a live bacterial vaccine vector for the outer surface protein A (OspA) of Borrelia burgdorferi and as model for other vaccines based on a rBCG vector. To construct the vaccine, a signal peptide derived from a mycobacterial lipoprotein was used to direct the export, and membrane-associated surface expression, of OspA in a standard strain of BCG (Connaught). The rBCG OspA vaccine was safe and immunogenic in several animal species, and protective in a mouse model of Lyme borreliosis. An intradermal injection (0.1 ml) of rBCG OspA was administered to 24 healthy adult volunteers sequentially at one of four dose levels, ranging from 2.0 x 10(4) CFU to 2 x 10(7) CFU, using a dose-escalation design. All volunteers were initially PPD-skin test and OspA antibody negative, and they were monitored for 2 years after immunization. Three volunteers had mild flu-like reactions 1-2 days after vaccination. Local ulceration and drainage at the site of injection, which occurred in 50% and 83% of volunteers in the two highest dose groups, persisted for 1-70 days before the ulcers healed. Most of the drainage samples yielded rBCG colonies that contained the OspA plasmid. Thirteen of 24 vaccinees, principally in the two highest dose groups, converted their PPD skin tests from negative to positive. None of the 24 volunteers developed OspA antibody. In conclusion, the current rBCG vaccine construct, the first such construct tested in humans, had a safety profile comparable to that of licensed BCG, but it did not elicit primary humoral responses to the vectored antigen.     

Effect of introduction of pentavalent vaccine as replacement for Diphtheria–Tetanus–Pertussis and Hepatitis B vaccines on vaccination uptake in a health facility in Nigeria

BackgroundThe introduction of a new vaccine into an immunization programme may affect the immunization system negatively or positively. The aim of this study is to determine the effect of the introduction of the pentavalent vaccine as replacement for DTP and Hepatitis B vaccines on timeliness, completion of the schedule and dropout rates among children attending a health facility.MethodologyThis was a retrospective cohort study which involved extracting immunization records of children attending the Institute of Child Health Child Welfare Clinic between June 2011 and May 2013. Pentavalent vaccine was introduced as a replacement for DTP and Hepatitis B vaccines in June 2012. The uptake, timeliness and dropout rates of different vaccines in the immunization schedule were determined for children who commenced immunization in the pre, peri and post introduction phases.ResultsA total of 1110 children were studied – 190, 410 and 510 who commenced vaccination in the pre, peri and post introduction phases of the pentavalent vaccine respectively. Uptake was significantly higher for all vaccines in the post introduction phase compared to pre and peri introduction phases (p < 0.001). Completion of the immunization schedule by 60.2% of the children who commenced vaccination in the post introduction phase was higher than the 31.6% and 41.7% for the pre and peri introduction phases respectively (p < 0.001). Significantly more visits were required to complete the schedule in the peri introduction phase compared to the pre and post introduction phases p < 0.001. Delay in receipt of the three doses of DTP/PENTA was significantly longer in the peri introduction phase compared to pre and post introduction phases.ConclusionThe introduction of pentavalent vaccine significantly improved uptake of vaccines and completion of the schedule but resulted in prolonged delay in receipt of vaccines during the introduction period.     

Increased measles–mumps–rubella (MMR) vaccine uptake in the context of a targeted immunisation campaign during a measles outbreak in a vaccine-reluctant community in England

Background

Following a measles outbreak in a vaccine-rejecting community between April and September 2011 in South-East England, local health agencies implemented a two-pronged measles–mumps–rubella (MMR) immunisation campaign from August to October offered at the local general practice where most cases were registered. The campaign included (a) accelerated vaccination of children earlier than scheduled (1st dose at 6–11 months, or 2nd dose at 18–39 months), (b) catch-up of those aged over 18 months who had had no MMR immunisations or were late for second MMR. We investigated the impact of the outbreak and campaign on the number of MMR doses given.

Materials and methods

In January 2012, we collected information on MMR vaccination for children registered at the practice aged 6 months–16 years on 1 August 2011, through the child health information system. We counted the number of MMR doses administered in 2011 and compared it to 2008–2010 data. We estimated the proportion vaccinated among the children eligible for the accelerated and catch-up campaign.

Results

The local practice administered 257 MMR doses in 2011, a 114% increase on the average for 2008–2010. Among children eligible for earlier MMR vaccination 5/26 (19%) received a first dose, and 34/57 (60%) a second dose. Among children eligible for catch-up, 20/329 (6%) received their first MMR and 39/121 (32%) their second. Of 1538 children, the proportion completely unimmunised for MMR declined by 3 percentage-points after the outbreak.

Discussion

Uptake of MMR vaccination significantly increased during the outbreak following the immunisation campaign. Those amenable to MMR vaccination seem to have benefited from the campaign more than those with no previous vaccinations. Future evaluations should address what made a few parents change their mind and have their children vaccinated for the first time during the outbreak.