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1.  A Phase I study evaluating the safety and immunogenicity of MVA85A, a candidate TB vaccine, in HIV-infected adults 
BMJ Open  2011;1(2):e000223.
Control of the tuberculosis (TB) epidemic is a global health priority and one that is likely to be achieved only through vaccination. The critical overlap with the HIV epidemic requires any effective TB vaccine regimen to be safe in individuals who are infected with HIV. The objectives of this clinical trial were to evaluate the safety and immunogenicity of a leading candidate TB vaccine, MVA85A, in healthy, HIV-infected adults.
This was an open-label Phase I trial, performed in 20 healthy HIV-infected, antiretroviral-naïve subjects. Two different doses of MVA85A were each evaluated as a single immunisation in 10 subjects, with 24 weeks of follow-up. The safety of MVA85A was assessed by clinical and laboratory markers, including regular CD4 counts and HIV RNA load measurements. Vaccine immunogenicity was assessed by ex vivo interferon γ (IFN-γ) ELISpot assays and flow-cytometric analysis.
MVA85A was safe in subjects with HIV infection, with an adverse-event profile comparable with historical data from previous trials in HIV-uninfected subjects. There were no clinically significant vaccine-related changes in CD4 count or HIV RNA load in any subjects, and no evidence from qPCR analyses to indicate that MVA85A vaccination leads to widespread preferential infection of vaccine-induced CD4 T cell populations. Both doses of MVA85A induced an antigen-specific IFN-γ response that was durable for 24 weeks, although of a lesser magnitude compared with historical data from HIV-uninfected subjects. The functional quality of the vaccine-induced T cell response in HIV-infected subjects was remarkably comparable with that observed in healthy HIV-uninfected controls, but less durable.
MVA85A is safe and immunogenic in healthy adults infected with HIV. Further safety and efficacy evaluation of this candidate vaccine in TB- and HIV-endemic areas is merited.
Article summary
Article focus
HIV infection increases susceptibility to TB, and globally, TB is the cause of death in up to half of AIDS deaths.
There is an urgent need for a safe and effective TB vaccine in HIV-infected people.
Key messages
MVA85A, a leading candidate TB vaccine, is safe and well tolerated in HIV-infected people and does not induce changes in either CD4 count or HIV RNA load.
MVA85A is immunogenic in HIV-infected people, and induces a similar immune profile to that seen in HIV-uninfected people, but the immunogenicity is less durable in HIV-infected people.
Strengths and limitations of this study
This is a Phase I study with 20 subjects, and further studies are needed in TB endemic countries in this important target population.
PMCID: PMC3221299  PMID: 22102640
2.  Safety and Immunogenicity of a New Tuberculosis Vaccine, MVA85A, in Mycobacterium tuberculosis–infected Individuals 
Rationale: An effective new tuberculosis (TB) vaccine regimen must be safe in individuals with latent TB infection (LTBI) and is a priority for global health care.
Objectives: To evaluate the safety and immunogenicity of a leading new TB vaccine, recombinant Modified Vaccinia Ankara expressing Antigen 85A (MVA85A) in individuals with LTBI.
Methods: An open-label, phase I trial of MVA85A was performed in 12 subjects with LTBI recruited from TB contact clinics in Oxford and London or by poster advertisements in Oxford hospitals. Patients were assessed clinically and had blood samples drawn for immunological analysis over a 52-week period after vaccination with MVA85A. Thoracic computed tomography scans were performed at baseline and at 10 weeks after vaccination. Safety of MVA85A was assessed by clinical, radiological, and inflammatory markers. The immunogenicity of MVA85A was assessed by IFNγ and IL-2 ELISpot assays and FACS.
Measurements and Main Results: MVA85A was safe in subjects with LTBI, with comparable adverse events to previous trials of MVA85A. There were no clinically significant changes in inflammatory markers or thoracic computed tomography scans after vaccination. MVA85A induced a strong antigen-specific IFN-γ and IL-2 response that was durable for 52 weeks. The magnitude of IFN-γ response was comparable to previous trials of MVA85A in bacillus Calmette-Guérin–vaccinated individuals. Antigen 85A–specific polyfunctional CD4+ T cells were detectable prior to vaccination with statistically significant increases in cell numbers after vaccination.
Conclusions: MVA85A is safe and highly immunogenic in individuals with LTBI. These results will facilitate further trials in TB-endemic areas.
Clinical trial registered with (NCT00456183).
PMCID: PMC2858810  PMID: 19151191
human; latent TB; vaccine; Koch
3.  Effect of vaccine dose on the safety and immunogenicity of a candidate TB vaccine, MVA85A, in BCG vaccinated UK adults 
Vaccine  2012;30(38):5616-5624.
► We compared 3 doses of a the candidate TB vaccine MVA85A. ► All doses of the vaccine were safe and induced a Th1 type immune response. ► The strongest and most sustained response was seen with the highest dose of MVA85A. ► A high dose of 1 × 108 PFU of MVA85A is safe and induces sustained immunity.
A non-randomised, open-label, Phase I safety and immunogenicity dose-finding study to assess the safety and immunogenicity of the candidate TB vaccine Modified Vaccinia virus Ankara expressing Antigen 85A (MVA85A) from Mycobacterium tuberculosis (MTB) in healthy adult volunteers previously vaccinated with BCG.
Healthy BCG-vaccinated volunteers were vaccinated with either 1 × 107 or 1 × 108 PFU of MVA85A. All adverse events were documented and antigen specific T cell responses were measured using an ex vivo IFN-γ ELISPOT assay. Safety and immunogenicity were compared between the 2 dose groups and with a previous trial in which a dose of 5 × 107 PFU MVA85A had been administered.
There were no serious adverse events recorded following administration of either 1 × 107 or 1 × 108 PFU of MVA85A. Systemic adverse events were more frequently reported following administration of 1 × 108 PFU of MVA85A when compared to either 5 × 107 or 1 × 107 PFU of MVA85A but were mild or moderate in severity and resolved completely within 7 days of immunisation. Antigen specific T cell responses as measured by the IFN-γ ELISPOT were significantly higher following immunisation in adults receiving 1 × 108 PFU compared to the 5 × 107 and 1 × 107 doses. Additionally, a broader range of Ag85A epitopes are detected following 1 × 108 PFU of MVA85A.
A higher dose of 1 × 108 PFU of MVA85A is well-tolerated, increases the frequency of IFN-γ secreting T cells detected following immunisation and broadens the range of Ag85A epitopes detected.
PMCID: PMC3424417  PMID: 22789508
Tuberculosis; Vaccine; BCG; MVA
4.  The Candidate TB Vaccine, MVA85A, Induces Highly Durable Th1 Responses 
PLoS ONE  2014;9(2):e87340.
Vaccination against tuberculosis (TB) should provide long-term protective immunity against Mycobacterium tuberculosis (M.tb). The current TB vaccine, Bacille Calmette-Guerin (BCG), protects against disseminated childhood TB, but protection against lung TB in adolescents and adults is variable and mostly poor. One potential reason for the limited durability of protection may be waning of immunity through gradual attrition of BCG-induced T cells. We determined if a MVA85A viral-vector boost could enhance the durability of mycobacteria-specific T cell responses above those induced by BCG alone.
We describe a long-term follow-up study of persons previously vaccinated with MVA85A. We performed a medical history and clinical examination, a tuberculin skin test and measured vaccine-specific T cell responses in persons previously enrolled as adults, adolescents, children or infants into three different Phase II trials, between 2005 and 2011.
Of 252 potential participants, 183 (72.6%) consented and completed the study visit. Vaccine-induced Ag85A-specific CD4+ T cell responses were remarkably persistent in healthy, HIV-uninfected adults, adolescents, children and infants, up to 6 years after MVA85A vaccination. Specific CD4+ T cells expressed surface markers consistent with either CD45RA−CCR7+ central memory or CD45RA−CCR7− effector memory T cells. Similarly durable Ag85A-specific CD4+ T cell responses were detected in HIV-infected persons who were on successful antiretroviral therapy when MVA85A was administered. By contrast, Ag85A-specific CD4+ T cell frequencies in untreated MVA85A-vaccinated HIV-infected persons were mostly undetectable 3–5 years after vaccination.
MVA85A induces remarkably durable T cell responses in immunocompetent persons. However, results from a recent phase IIb trial of MVA85A, conducted in infants from the same geographic area and study population, showed no vaccine efficacy, suggesting that these durable T cell responses do not enhance BCG-induced protection against TB in infants.
PMCID: PMC3911992  PMID: 24498312
5.  A neonatal oral Mycobacterium tuberculosis-SIV prime / intramuscular MVA-SIV boost combination vaccine induces both SIV and Mtb-specific immune responses in infant macaques 
Trials in vaccinology  2013;2:53-63.
Mother-to-child-transmission of HIV by breast-feeding remains a major obstacle in the eradication of HIV infection. Compared to adults, HIV-infected infants have more rapid disease and show higher susceptibility to co-infections like tuberculosis (TB). Although the Bacille Calmette-Guérin vaccine can be administered at birth to protect against TB, BCG can disseminate in HIV-infected infants and increase mortality. Thus, a pediatric combination vaccine to stop both HIV and TB infection in infants is urgently needed.
Towards the goal of developing a pediatric combination HIV-TB vaccine to prevent both oral HIV acquisition by breast-feeding and TB infection, we tested and optimized an immunization regimen using a novel live attenuated Mycobacterium tuberculosis vaccine engineered to express simian immunodeficiency (SIV) antigens followed by heterologous MVA-SIV boosting in the infant macaque model. A single oral dose of the attenuated Mtb-SIV vaccine strain mc26435 during the first week of life was sufficient to induce persistent TB-specific immune responses. SIV-specific immunity was induced at low but comparable magnitudes after oral or intradermal priming, and was enhanced following MVA-SIV boosts. T cell responses were most pronounced in intestinal tissues and oral lymph nodes. Importantly, in addition to plasma SIV-specific IgG and IgA antibodies, infant macaques developed mucosal SIV-specific IgA in saliva and intestinal IgA and IgG. While future SIV and Mtb challenge studies will be needed to determine the protective efficacy of the Mtb-SIV / MVA-SIV vaccine, infants at high risk for oral HIV acquisition by breast-feeding and TB infection could profoundly benefit from an effective combination vaccine.
PMCID: PMC3894789  PMID: 24454591
6.  A Novel Poxvirus-Based Vaccine, MVA-CHIKV, Is Highly Immunogenic and Protects Mice against Chikungunya Infection 
Journal of Virology  2014;88(6):3527-3547.
There is a need to develop a single and highly effective vaccine against the emerging chikungunya virus (CHIKV), which causes a severe disease in humans. Here, we have generated and characterized the immunogenicity profile and the efficacy of a novel CHIKV vaccine candidate based on the highly attenuated poxvirus vector modified vaccinia virus Ankara (MVA) expressing the CHIKV C, E3, E2, 6K, and E1 structural genes (termed MVA-CHIKV). MVA-CHIKV was stable in cell culture, expressed the CHIKV structural proteins, and triggered the cytoplasmic accumulation of Golgi apparatus-derived membranes in infected human cells. Furthermore, MVA-CHIKV elicited robust innate immune responses in human macrophages and monocyte-derived dendritic cells, with production of beta interferon (IFN-β), proinflammatory cytokines, and chemokines. After immunization of C57BL/6 mice with a homologous protocol (MVA-CHIKV/MVA-CHIKV), strong, broad, polyfunctional, and durable CHIKV-specific CD8+ T cell responses were elicited. The CHIKV-specific CD8+ T cells were preferentially directed against E1 and E2 proteins and, to a lesser extent, against C protein. CHIKV-specific CD8+ memory T cells of a mainly effector memory phenotype were also induced. The humoral arm of the immune system was significantly induced, as MVA-CHIKV elicited high titers of neutralizing antibodies against CHIKV. Remarkably, a single dose of MVA-CHIKV protected all mice after a high-dose challenge with CHIKV. In summary, MVA-CHIKV is an effective vaccine against chikungunya virus infection that induced strong, broad, highly polyfunctional, and long-lasting CHIKV-specific CD8+ T cell responses, together with neutralizing antibodies against CHIKV. These results support the consideration of MVA-CHIKV as a potential vaccine candidate against CHIKV.
IMPORTANCE We have developed a novel vaccine candidate against chikungunya virus (CHIKV) based on the highly attenuated poxvirus vector modified vaccinia virus Ankara (MVA) expressing the CHIKV C, E3, E2, 6K, and E1 structural genes (termed MVA-CHIKV). Our findings revealed that MVA-CHIKV is a highly effective vaccine against chikungunya virus, with a single dose of the vaccine protecting all mice after a high-dose challenge with CHIKV. Furthermore, MVA-CHIKV is highly immunogenic, inducing strong innate responses: high, broad, polyfunctional, and long-lasting CHIKV-specific CD8+ T cell responses, together with neutralizing antibodies against CHIKV. This work provides a potential vaccine candidate against CHIKV.
PMCID: PMC3957920  PMID: 24403588
7.  Phase I Safety and Immunogenicity Evaluation of MVA-CMDR, a Multigenic, Recombinant Modified Vaccinia Ankara-HIV-1 Vaccine Candidate 
PLoS ONE  2010;5(11):e13983.
We conducted a Phase I randomized, dose-escalation, route-comparison trial of MVA-CMDR, a candidate HIV-1 vaccine based on a recombinant modified vaccinia Ankara viral vector expressing HIV-1 genes env/gag/pol. The HIV sequences were derived from circulating recombinant form CRF01_AE, which predominates in Thailand. The objective was to evaluate safety and immunogenicity of MVA-CMDR in human volunteers in the US and Thailand.
Methodology/Principal Findings
MVA-CMDR or placebo was administered intra-muscularly (IM; 107 or 108 pfu) or intradermally (ID; 106 or 107 pfu) at months 0, 1 and 3, to 48 healthy volunteers at low risk for HIV-1 infection. Twelve volunteers in each dosage group were randomized to receive MVA-CMDR or placebo (10∶2). Volunteers were actively monitored for local and systemic reactogenicity and adverse events post vaccination. Cellular immunogenicity was assessed by a validated IFNγ Elispot assay, an intracellular cytokine staining assay, lymphocyte proliferation and a 51Cr-release assay. Humoral immunogenicity was assessed by ADCC for gp120 and binding antibody ELISAs for gp120 and p24. MVA-CMDR was safe and well tolerated with no vaccine related serious adverse events. Cell-mediated immune responses were: (i) moderate in magnitude (median IFNγ Elispot of 78 SFC/106 PBMC at 108 pfu IM), but high in response rate (70% 51Cr-release positive; 90% Elispot positive; 100% ICS positive, at 108 pfu IM); (ii) predominantly HIV Env-specific CD4+ T cells, with a high proliferative capacity and durable for at least 6 months (100% LPA response rate by the IM route); (iv) dose- and route-dependent with 108 pfu IM being the most immunogenic treatment. Binding antibodies against gp120 and p24 were detectable in all vaccination groups with ADCC capacity detectable at the highest dose (40% positive at 108 pfu IM).
MVA-CMDR delivered both intramuscularly and intradermally was safe, well-tolerated and elicited durable cell-mediated and humoral immune responses.
Trial Registration NCT00376090
PMCID: PMC2981570  PMID: 21085591
8.  Safety and immunogenicity of a new tuberculosis vaccine, MVA85A, in healthy adults in South Africa1 
The Journal of infectious diseases  2008;198(4):544-552.
The efficacy of BCG may be enhanced by heterologous vaccination strategies that boost the BCG-primed immune response. One leading booster vaccine, MVA85A, has shown promising safety and immunogenicity in UK human trials. We investigated the safety and immunogenicity of MVA85A in mycobacteria-exposed, but Mycobacterium tuberculosis-uninfected, healthy adults from a TB-endemic region of South Africa.
Twenty-four adults were vaccinated with MVA85A. All subjects were followed up for one year for adverse events and for immunological assessment.
MVA85A vaccination was well tolerated and induced potent T cell responses, measured by IFN-γ ELISPOT assay, which exceeded pre-vaccination levels up to 364 days after vaccination. BCG-specific CD4+ T cells boosted by MVA85A comprised of multiple populations expressing combinations of IFN-γ, TNF-α, IL-2 and IL-17, as measured by polychromatic flow cytometry. IFN-γ expressing and polyfunctional IFN-γ+TNF-α+IL-2+ CD4+ T cells were boosted during the peak BCG-specific response 7 days post-vaccination.
The excellent safety profile and quantitative and qualitative immunogenicity data strongly support further trials to assess the efficacy of MVA85A as a boosting vaccine in TB endemic countries.
PMCID: PMC2822902  PMID: 18582195
Vaccination; tuberculosis; T cells; MVA85A; South Africa
9.  Safety and immunogenicity of a candidate tuberculosis vaccine MVA85A delivered by aerosol in BCG-vaccinated healthy adults: a phase 1, double-blind, randomised controlled trial 
The Lancet. Infectious Diseases  2014;14(10):939-946.
Intradermal MVA85A, a candidate vaccine against tuberculosis, induces high amounts of Ag85A-specific CD4 T cells in adults who have already received the BCG vaccine, but aerosol delivery of this vaccine might offer immunological and logistical advantages. We did a phase 1 double-blind trial to compare the safety and immunogenicity of aerosol-administered and intradermally administered MVA85A
In this phase 1, double-blind, proof-of-concept trial, 24 eligible BCG-vaccinated healthy UK adults were randomly allocated (1:1) by sequentially numbered, sealed, opaque envelopes into two groups: aerosol MVA85A and intradermal saline placebo or intradermal MVA85A and aerosol saline placebo. Participants, the bronchoscopist, and immunologists were masked to treatment assignment. The primary outcome was safety, assessed by the frequency and severity of vaccine-related local and systemic adverse events. The secondary outcome was immunogenicity assessed with laboratory markers of cell-mediated immunity in blood and bronchoalveolar lavage samples. Safety and immunogenicity were assessed for 24 weeks after vaccination. Immunogenicity to both insert Ag85A and vector modified vaccinia virus Ankara (MVA) was assessed by ex-vivo interferon-γ ELISpot and serum ELISAs. Since all participants were randomised and vaccinated according to protocol, our analyses were per protocol. This trial is registered with, number NCT01497769.
Both administration routes were well tolerated and immunogenic. Respiratory adverse events were rare and mild. Intradermal MVA85A was associated with expected mild local injection-site reactions. Systemic adverse events did not differ significantly between the two groups. Three participants in each group had no vaccine-related systemic adverse events; fatigue (11/24 [46%]) and headache (10/24 [42%]) were the most frequently reported symptoms. Ag85A-specific systemic responses were similar across groups. Ag85A-specific CD4 T cells were detected in bronchoalveolar lavage cells from both groups and responses were higher in the aerosol group than in the intradermal group. MVA-specific cellular responses were detected in both groups, whereas serum antibodies to MVA were only detectable after intradermal administration of the vaccine.
Further clinical trials assessing the aerosol route of vaccine delivery are merited for tuberculosis and other respiratory pathogens.
The Wellcome Trust and Oxford Radcliffe Hospitals Biomedical Research Centre.
PMCID: PMC4178237  PMID: 25151225
10.  Boosting BCG with Recombinant Modified Vaccinia Ankara Expressing Antigen 85A: Different Boosting Intervals and Implications for Efficacy Trials 
PLoS ONE  2007;2(10):e1052.
To investigate the safety and immunogenicity of boosting BCG with modified vaccinia Ankara expressing antigen 85A (MVA85A), shortly after BCG vaccination, and to compare this first with the immunogenicity of BCG vaccination alone and second with a previous clinical trial where MVA85A was administered more than 10 years after BCG vaccination.
There are two clinical trials reported here: a Phase I observational trial with MVA85A; and a Phase IV observational trial with BCG. These clinical trials were all conducted in the UK in healthy, HIV negative, BCG naïve adults. Subjects were vaccinated with BCG alone; or BCG and then subsequently boosted with MVA85A four weeks later (short interval). The outcome measures, safety and immunogenicity, were monitored for six months. The immunogenicity results from this short interval BCG prime–MVA85A boost trial were compared first with the BCG alone trial and second with a previous clinical trial where MVA85A vaccination was administered many years after vaccination with BCG.
MVA85A was safe and highly immunogenic when administered to subjects who had recently received BCG vaccination. When the short interval trial data presented here were compared with the previous long interval trial data, there were no significant differences in the magnitude of immune responses generated when MVA85A was administered shortly after, or many years after BCG vaccination.
The clinical trial data presented here provides further evidence of the ability of MVA85A to boost BCG primed immune responses. This boosting potential is not influenced by the time interval between prior BCG vaccination and boosting with MVA85A. These findings have important implications for the design of efficacy trials with MVA85A. Boosting BCG induced anti-mycobacterial immunity in either infancy or adolescence are both potential applications for this vaccine, given the immunological data presented here.
Trial Registration NCT00427453 (short boosting interval), NCT00427830 (long boosting interval), NCT00480714 (BCG alone)
PMCID: PMC2034536  PMID: 17957238
11.  Safety and immunogenicity of an FP9-vectored candidate tuberculosis vaccine (FP85A), alone and with candidate vaccine MVA85A in BCG-vaccinated healthy adults 
The safety and immunogenicity of a new candidate tuberculosis (TB) vaccine, FP85A was evaluated alone and in heterologous prime-boost regimes with another candidate TB vaccine, MVA85A. This was an open label, non-controlled, non-randomized Phase I clinical trial. Healthy previously BCG-vaccinated adult subjects were enrolled sequentially into three groups and vaccinated with FP85A alone, or both FP85A and MVA85A, with a four week interval between vaccinations. Passive and active data on adverse events were collected. Immunogenicity was evaluated by Enzyme Linked Immunospot (ELISpot), flow cytometry and Enzyme Linked Immunosorbent assay (ELISA). Most adverse events were mild and there were no vaccine-related serious adverse events. FP85A vaccination did not enhance antigen 85A-specific cellular immunity. When MVA85A vaccination was preceded by FP85A vaccination, cellular immune responses were lower compared with when MVA85A vaccination was the first immunisation. MVA85A vaccination, but not FP85A vaccination, induced anti-MVA IgG antibodies. Both MVA85A and FP85A vaccinations induced anti-FP9 IgG antibodies. In conclusion, FP85A vaccination was well tolerated but did not induce antigen-specific cellular immune responses. We hypothesize that FP85A induced anti-FP9 IgG antibodies with cross-reactivity for MVA85A, which may have mediated inhibition of the immune response to subsequent MVA85A. identification number: NCT00653770
PMCID: PMC3667946  PMID: 23143773
phase I clinical trial; tuberculosis vaccines; heterologous prime-boost regimes; poxvirus-vectored subunit vaccines
12.  Dual Neonate Vaccine Platform against HIV-1 and M. tuberculosis 
PLoS ONE  2011;6(5):e20067.
Acquired immunodeficiency syndrome and tuberculosis (TB) are two of the world's most devastating diseases. The first vaccine the majority of infants born in Africa receive is Mycobacterium bovis bacillus Calmette-Guérin (BCG) as a prevention against TB. BCG protects against disseminated disease in the first 10 years of life, but provides a variable protection against pulmonary TB and enhancing boost delivered by recombinant modified vaccinia virus Ankara (rMVA) expressing antigen 85A (Ag85A) of M. tuberculosis is currently in phase IIb evaluation in African neonates. If the newborn's mother is positive for human immunodeficiency virus type 1 (HIV-1), the baby is at high risk of acquiring HIV-1 through breastfeeding. We suggested that a vaccination consisting of recombinant BCG expressing HIV-1 immunogen administered at birth followed by a boost with rMVA sharing the same immunogen could serve as a strategy for prevention of mother-to-child transmission of HIV-1 and rMVA expressing an African HIV-1-derived immunogen HIVA is currently in phase I trials in African neonates. Here, we aim to develop a dual neonate vaccine platform against HIV-1 and TB consisting of BCG.HIVA administered at birth followed by a boost with MVA.HIVA.85A. Thus, mMVA.HIVA.85A and sMVA.HIVA.85A vaccines were constructed, in which the transgene transcription is driven by either modified H5 or short synthetic promoters, respectively, and tested for immunogenicity alone and in combination with BCG.HIVA222. mMVA.HIVA.85A was produced markerless and thus suitable for clinical manufacture. While sMVA.HIVA.85A expressed higher levels of the immunogens, it was less immunogenic than mMVA.HIVA.85A in BALB/c mice. A BCG.HIVA222–mMVA.HIVA.85A prime-boost regimen induced robust T cell responses to both HIV-1 and M. tuberculosis. Therefore, proof-of-principle for a dual anti-HIV-1/M. tuberculosis infant vaccine platform is established. Induction of immune responses against these pathogens soon after birth is highly desirable and may provide a basis for lifetime protection maintained by boosts later in life.
PMCID: PMC3094449  PMID: 21603645
13.  Highly Persistent and Effective Prime/Boost Regimens against Tuberculosis That Use a Multivalent Modified Vaccine Virus Ankara-Based Tuberculosis Vaccine with Interleukin-15 as a Molecular Adjuvant ▿  
Novel immunization strategies are needed to enhance the global control of tuberculosis (TB). In this study, we assessed the immunizing activity of a recombinant modified vaccinia Ankara (MVA) construct (MVA/IL-15/5Mtb) which overexpresses five Mycobacterium tuberculosis antigens (antigen 85A, antigen 85B, ESAT6, HSP60, and Mtb39), as well as the molecular adjuvant interleukin-15 (IL-15). Homologous prime/boost studies showed that the MVA/IL-15/5Mtb vaccine induced moderate but highly persistent protective immune responses for at least 16 months after the initial vaccination and that the interval between the prime and boost did not significantly alter vaccine-induced antituberculosis protective immunity. At 16 months, when the Mycobacterium bovis BCG and MVA/IL-15/5Mtb vaccine-induced protection was essentially equivalent, the protective responses after a tuberculous challenge were associated with elevated levels of gamma interferon (IFN-γ), IL-17F, Cxcl9, and Cxcl10. To amplify the immunizing potential of the MVA/IL-15/5Mtb vaccine, a heterologous prime/boost regimen was tested using an ESAT6-antigen 85B (E6-85) fusion protein formulated in dimethyldiotacylammonium bromide/monophosphoryl lipid A (DDA/MPL) adjuvant as the priming vaccine and the MVA/IL-15/5Mtb recombinant virus as the boosting agent. When MVA/IL-15/5Mtb vaccine boosting was done at 2 or 6 months following the final fusion protein injections, the prime/boost regimen evoked protective responses against an aerogenic M. tuberculosis challenge which was equivalent to that induced by BCG immunization. Long-term memory after immunization with the E6-85-MVA/IL-15/5Mtb combination regimen was associated with the induction of monofunctional CD4 and CD8 IFN-γ-producing T cells and multifunctional CD4 and CD8 T cells expressing IFN-γ/tumor necrosis factor alpha (TNF-α), TNF-α/IL-2, and IFN-γ/TNF-α/IL-2. In contrast, BCG-induced protection was characterized by fewer CD4 and CD8 monofunctional T cells expressing IFN-γ and only IFN-γ/TNF-α and IFN-γ/TNF-α/IL-2 expressing multifunctional T (MFT) cells. Taken together, these results suggest that a heterologous prime/boost protocol using an MVA-based tuberculosis vaccines to boost after priming with TB protein/adjuvant preparations should be considered when designing long-lived TB immunization strategies.
PMCID: PMC2863387  PMID: 20357059
14.  A Phase I Randomized Clinical Trial of Candidate Human Immunodeficiency Virus type 1 Vaccine MVA.HIVA Administered to Gambian Infants 
PLoS ONE  2013;8(10):e78289.
A vaccine to decrease transmission of human immunodeficiency virus type 1 (HIV-1) during breast-feeding would complement efforts to eliminate infant HIV-1 infection by antiretroviral therapy. Relative to adults, infants have distinct immune development, potentially high-risk of transmission when exposed to HIV-1 and rapid progression to AIDS when infected. To date, there have been only three published HIV-1 vaccine trials in infants.
Trial Design
We conducted a randomized phase I clinical trial PedVacc 001 assessing the feasibility, safety and immunogenicity of a single dose of candidate vaccine MVA.HIVA administered intramuscularly to 20-week-old infants born to HIV-1-negative mothers in The Gambia.
Infants were followed to 9 months of age with assessment of safety, immunogenicity and interference with Expanded Program on Immunization (EPI) vaccines. The trial is the first stage of developing more complex prime-boost vaccination strategies against breast milk transmission of HIV-1.
From March to October 2010, 48 infants (24 vaccine and 24 no-treatment) were enrolled with 100% retention. The MVA.HIVA vaccine was safe with no difference in adverse events between vaccinees and untreated infants. Two vaccine recipients (9%) and no controls had positive ex vivo interferon-γ ELISPOT assay responses. Antibody levels elicited to the EPI vaccines, which included diphtheria, tetanus, whole-cell pertussis, hepatitis B virus, Haemophilus influenzae type b and oral poliovirus, reached protective levels for the vast majority and were similar between the two arms.
A single low-dose of MVA.HIVA administered to 20-week-old infants in The Gambia was found to be safe and without interference with the induction of protective antibody levels by EPI vaccines, but did not alone induce sufficient HIV-1-specific responses. These data support the use of MVA carrying other transgenes as a boosting vector within more complex prime-boost vaccine strategies against transmission of HIV-1 and/or other infections in this age group.
Trial Registration NCT00982579
The Pan African Clinical Trials Registry PACTR2008120000904116
PMCID: PMC3813444  PMID: 24205185
15.  Immunisation with BCG and recombinant MVA85A induces long-lasting, polyfunctional Mycobacterium tuberculosis-specific CD4+ memory T lymphocyte populations 
European journal of immunology  2007;37(11):3089-3100.
In the search for effective vaccines against intracellular pathogens such as HIV, tuberculosis and malaria, recombinant viral vectors are increasingly being used to boost previously primed T cell responses. Published data have shown prime-boost vaccination with BCG-MVA85A (modified vaccinia virus Ankara expressing antigen 85A) to be highly immunogenic in humans as measured by ex vivo IFN-γ ELISPOT. Here, we used polychromatic flow cytometry to investigate the phenotypic and functional profile of these vaccine-induced Mycobacterium tuberculosis (M.tb) antigen 85A-specific responses in greater detail. Promisingly, antigen 85A-specific CD4+ T cells were found to be highly polyfunctional, producing IFN-γ, TNF-α, IL-2 and MIP-1β. Surface staining showed the responding CD4+ T cells to be relatively immature (CD45RO+ CD27intCD57−); this observation was supported by the robust proliferative responses observed following antigenic stimulation. Furthermore, these phenotypic and functional properties were independent of clonotypic composition and epitope specificity, which was maintained through the different phases of the vaccine-induced immune response. Overall, these data strongly support the use of MVA85A in humans as a boosting agent to expand polyfunctional M.tb-specific CD4+ T cells capable of significant secondary responses.
PMCID: PMC2365909  PMID: 17948267
CD4+ T cells; Human; Recombinant viral vectors; Tuberculosis
16.  Immunogenic Profiling in Mice of a HIV/AIDS Vaccine Candidate (MVA-B) Expressing Four HIV-1 Antigens and Potentiation by Specific Gene Deletions 
PLoS ONE  2010;5(8):e12395.
The immune parameters of HIV/AIDS vaccine candidates that might be relevant in protection against HIV-1 infection are still undefined. The highly attenuated poxvirus strain MVA is one of the most promising vectors to be use as HIV-1 vaccine. We have previously described a recombinant MVA expressing HIV-1 Env, Gag, Pol and Nef antigens from clade B (referred as MVA-B), that induced HIV-1-specific immune responses in different animal models and gene signatures in human dendritic cells (DCs) with immunoregulatory function.
Methodology/Principal Findings
In an effort to characterize in more detail the immunogenic profile of MVA-B and to improve its immunogenicity we have generated a new vector lacking two genes (A41L and B16R), known to counteract host immune responses by blocking the action of CC-chemokines and of interleukin 1β, respectively (referred as MVA-B ΔA41L/ΔB16R). A DNA prime/MVA boost immunization protocol was used to compare the adaptive and memory HIV-1 specific immune responses induced in mice by the parental MVA-B and by the double deletion mutant MVA-B ΔA41L/ΔB16R. Flow cytometry analysis revealed that both vectors triggered HIV-1-specific CD4+ and CD8+ T cells, with the CD8+ T-cell compartment responsible for >91.9% of the total HIV-1 responses in both immunization groups. However, MVA-B ΔA41L/ΔB16R enhanced the magnitude and polyfunctionality of the HIV-1-specific CD4+ and CD8+ T-cell immune responses. HIV-1-specific CD4+ T-cell responses were polyfunctional and preferentially Env-specific in both immunization groups. Significantly, while MVA-B induced preferentially Env-specific CD8+ T-cell responses, MVA-B ΔA41L/ΔB16R induced more GPN-specific CD8+ T-cell responses, with an enhanced polyfunctional pattern. Both vectors were capable of producing similar levels of antibodies against Env.
These findings revealed that MVA-B and MVA-B ΔA41L/ΔB16R induced in mice robust, polyfunctional and durable T-cell responses to HIV-1 antigens, but the double deletion mutant showed enhanced magnitude and quality of HIV-1 adaptive and memory responses. Our observations are relevant in the immune evaluation of MVA-B and on improvements of MVA vectors as HIV-1 vaccines.
PMCID: PMC2927552  PMID: 20811493
17.  Two Doses of Candidate TB Vaccine MVA85A in Antiretroviral Therapy (ART) Naïve Subjects Gives Comparable Immunogenicity to One Dose in ART+ Subjects 
PLoS ONE  2013;8(6):e67177.
Tuberculosis (TB) is a global public health problem exacerbated by the HIV epidemic. Here we evaluate a candidate TB vaccine, MVA85A, in a Phase I study in HIV-infected adults in Senegal. 24 patients were enrolled: Group 1∶12, antiretroviral therapy (ART) naïve, adults, with CD4 counts >300 and HIV RNA load <100 000 copies/ml. Group 2∶12 adults, stable on ART, with CD4 counts >300, and an undetectable HIV RNA load. Safety was evaluated by occurrence of local and systemic adverse events (AEs) and by monitoring of CD4 count, HIV RNA load, haematology and biochemistry. Immunogenicity was evaluated by ex-vivo interferon-gamma ELISpot assay. 87.7% of AEs were mild; 11.6% were moderate; and 0.7% were severe. 29.2% of AEs were systemic; 70.8% were expected local AEs. There were no vaccine-related Serious Adverse Events (SAEs) or clinically significant effects on HIV RNA load or CD4 count. In ART naive subjects, the first MVA85A immunisation induced a significant immune response at 1 and 4 weeks post-immunisation, which contracted to baseline by 12 weeks. Durability of immunogenicity in subjects on ART persisted out to 24 weeks post-vaccination. A second dose of MVA85A at 12 months enhanced immunogenicity in ART naïve subjects. Subjects on ART had higher responses after the first vaccination compared with ART naïve subjects; responses were comparable after 2 immunisations. In conclusion, MVA85A is well-tolerated and immunogenic in HIV-infected subjects in Senegal. A two dose regimen in ART naïve subjects is comparable in immunogenicity to a single dose in subjects on ART. trial identifier NCT00731471.
PMCID: PMC3696007  PMID: 23840618
18.  Improving Adaptive and Memory Immune Responses of an HIV/AIDS Vaccine Candidate MVA-B by Deletion of Vaccinia Virus Genes (C6L and K7R) Blocking Interferon Signaling Pathways 
PLoS ONE  2013;8(6):e66894.
Poxvirus vector Modified Vaccinia Virus Ankara (MVA) expressing HIV-1 Env, Gag, Pol and Nef antigens from clade B (termed MVA-B) is a promising HIV/AIDS vaccine candidate, as confirmed from results obtained in a prophylactic phase I clinical trial in humans. To improve the immunogenicity elicited by MVA-B, we have generated and characterized the innate immune sensing and the in vivo immunogenicity profile of a vector with a double deletion in two vaccinia virus (VACV) genes (C6L and K7R) coding for inhibitors of interferon (IFN) signaling pathways. The innate immune signals elicited by MVA-B deletion mutants (MVA-B ΔC6L and MVA-B ΔC6L/K7R) in human macrophages and monocyte-derived dendritic cells (moDCs) showed an up-regulation of the expression of IFN-β, IFN-α/β-inducible genes, TNF-α, and other cytokines and chemokines. A DNA prime/MVA boost immunization protocol in mice revealed that these MVA-B deletion mutants were able to improve the magnitude and quality of HIV-1-specific CD4+ and CD8+ T cell adaptive and memory immune responses, which were mostly mediated by CD8+ T cells of an effector phenotype, with MVA-B ΔC6L/K7R being the most immunogenic virus recombinant. CD4+ T cell responses were mainly directed against Env, while GPN-specific CD8+ T cell responses were induced preferentially by the MVA-B deletion mutants. Furthermore, antibody levels to Env in the memory phase were slightly enhanced by the MVA-B deletion mutants compared to the parental MVA-B. These findings revealed that double deletion of VACV genes that act blocking intracellularly the IFN signaling pathway confers an immunological benefit, inducing innate immune responses and increases in the magnitude, quality and durability of the HIV-1-specific T cell immune responses. Our observations highlighted the immunomodulatory role of the VACV genes C6L and K7R, and that targeting common pathways, like IRF3/IFN-β signaling, could be a general strategy to improve the immunogenicity of poxvirus-based vaccine candidates.
PMCID: PMC3694958  PMID: 23826170
19.  Safety and Immunogenicity of Boosting BCG Vaccinated Subjects with BCG: Comparison with Boosting with a New TB Vaccine, MVA85A 
PLoS ONE  2009;4(6):e5934.
To investigate the safety and immunogenicity of a booster BCG vaccination delivered intradermally in healthy, BCG vaccinated subjects and to compare with a previous clinical trial where BCG vaccinated subjects were boosted with a new TB vaccine, MVA85A.
Phase I open label observational trial, in the UK. Healthy, HIV-negative, BCG vaccinated adults were recruited and vaccinated with BCG. The primary outcome was safety; the secondary outcome was cellular immune responses to antigen 85, overlapping peptides of antigen 85A and tuberculin purified protein derivative (PPD) detected by ex vivo interferon-gamma (IFN-γ) ELISpot assay and flow cytometry.
Results and Conclusions
BCG revaccination (BCG-BCG) was well tolerated, and boosting of pre-existing PPD-specific T cell responses was observed. However, when these results were compared with data from a previous clinical trial, where BCG was boosted with MVA85A (BCG-MVA85A), MVA85A induced significantly higher levels (>2-fold) of antigen 85-specific CD4+ T cells (both antigen and peptide pool responses) than boosting with BCG, up to 52 weeks post-vaccination (p = 0.009). To identify antigen 85A-specific CD8+ T cells that were not detectable by ex vivo ELISpot and flow cytometry, dendritic cells (DC) were used to amplify CD8+ T cells from PBMC samples. We observed low, but detectable levels of antigen 85A-specific CD8+ T cells producing IFNγ (1.5% of total CD8 population) in the BCG primed subjects after BCG boosting in 1 (20%) of 5 subjects. In contrast, in BCG-MVA85A vaccinated subjects, high levels of antigen 85A-specific CD8+ T cells (up to 14% total CD8 population) were observed after boosting with MVA85A, in 4 (50%) of 8 subjects evaluated.
In conclusion, revaccination with BCG resulted in modest boosting of pre-existing immune responses to PPD and antigen 85, but vaccination with BCG-MVA85A induced a significantly higher response to antigen 85 and generated a higher frequency of antigen 85A-specific CD8+ T cells.
Trial Registration NCT00654316 NCT00427830
PMCID: PMC2694271  PMID: 19529780
20.  A prime/boost DNA/Modified vaccinia virus Ankara vaccine expressing recombinant Leishmania DNA encoding TRYP is safe and immunogenic in outbred dogs, the reservoir of zoonotic visceral leishmaniasis 
Vaccine  2009;27(7):1080-1086.
Previous studies demonstrated safety, immunogenicity and efficacy of DNA/modified vaccinia virus Ankara (MVA) prime/boost vaccines expressing tryparedoxin peroxidase (TRYP) and Leishmania homologue of the mammalian receptor for activated C kinase (LACK) against Leishmania major challenge in mice, which was consistent with results from TRYP protein/adjuvant combinations in non-human primates. This study aimed to conduct safety and immunogenicity trials of these DNA/MVA vaccines in dogs, the natural reservoir host of Leishmania infantum, followed-up for 4 months post-vaccination.
In a cohort of 22 uninfected outbred dogs, blinded randomised administration of 1000 μg (high dose) or 100 μg (low dose) DNA prime (day 0) and 1 × 108 pfu MVA boost (day 28) was shown to be safe and showed no clinical side effects. High dose DNA/MVA vaccinated TRYP dogs produced statistically higher mean levels of the type-1 pro-inflammatory cytokine IFN-γ than controls in whole blood assays (WBA) stimulated with the recombinant vaccine antigen TRYP, up to the final sampling at day 126, and in the absence of challenge with Leishmania. TRYP vaccinated dogs also demonstrated significantly higher TRYP-specific total IgG and IgG2 subtype titres than in controls, and positive in vivo intradermal reactions at day 156 in the absence of natural infection, observed in 6/8 TRYP vaccinated dogs. No significant increases in IFN-γ in LACK-stimulated WBA, or in LACK-specific IgG levels, were detected in LACK vaccinated dogs compared to controls, and only 2/9 LACK vaccinated dogs demonstrated DTH responses at day 156. In all groups, IgG1 subclass responses and antigen-specific stimulation of IL-10 were similar to controls demonstrating an absence of Th2/Treg response, as expected in the absence of in vivo restimulation or natural/experimental challenge with Leishmania.
These collective results indicate significant antigen-specific type-1 responses and in vivo memory phase cellular immune responses, consistent with superior potential for protective vaccine immunogenicity of DNA/MVA TRYP over LACK.
PMCID: PMC2663027  PMID: 19095029
Leishmania infantum; Tryparedoxin peroxidase; Prime/boost DNA/MVA vaccination
21.  Deletion of the Vaccinia Virus N2L Gene Encoding an Inhibitor of IRF3 Improves the Immunogenicity of Modified Vaccinia Virus Ankara Expressing HIV-1 Antigens 
Journal of Virology  2014;88(6):3392-3410.
A modified vaccinia virus Ankara poxvirus vector expressing the HIV-1 Env, Gag, Pol, and Nef antigens from clade B (MVA-B) is currently being tested in clinical trials. To improve its immunogenicity, we have generated and characterized the immune profile of MVA-B containing a deletion of the vaccinia viral gene N2L, which codes for an inhibitor of IRF3 (MVA-B ΔN2L). Deletion of N2L had no effect on virus growth kinetics or on the expression of HIV-1 antigens; hence, the N2 protein is not essential for MVA replication. The innate immune responses triggered by MVA-B ΔN2L revealed an increase in beta interferon, proinflammatory cytokines, and chemokines. Mouse prime-boost protocols showed that MVA-B ΔN2L improves the magnitude and polyfunctionality of HIV-1-specific CD4+ and CD8+ T cell adaptive and memory immune responses, with most of the HIV-1 responses mediated by CD8+ T cells. In the memory phase, HIV-1-specific CD8+ T cells with an effector phenotype were predominant and in a higher percentage with MVA-B ΔN2L than with MVA-B. In both immunization groups, CD4+ and CD8+ T cell responses were directed mainly against Env. Furthermore, MVA-B ΔN2L in the memory phase enhanced levels of antibody against Env. For the vector immune responses, MVA-B ΔN2L induced a greater magnitude and polyfunctionality of VACV-specific CD8+ T memory cells than MVA-B, with an effector phenotype. These results revealed the immunomodulatory role of N2L, whose deletion enhanced the innate immunity and improved the magnitude and quality of HIV-1-specific T cell adaptive and memory immune responses. These findings are relevant for the optimization of poxvirus vectors as vaccines.
IMPORTANCE On the basis of the limited efficacy of the RV144 phase III clinical trial, new optimized poxvirus vectors as vaccines against HIV/AIDS are needed. Here we have generated and characterized a new HIV/AIDS vaccine candidate on the basis of the poxvirus MVA vector expressing HIV-1 Env, Gag, Pol, and Nef antigens (MVA-B) and containing a deletion in the vaccinia virus N2L gene. Our findings revealed the immunomodulatory role of N2L and proved that its deletion from the MVA-B vector triggered an enhanced innate immune response in human macrophages and monocyte-derived dendritic cells. Furthermore, in immunized mice, MVA-B ΔN2L induced improvements in the magnitude and quality of adaptive and memory HIV-1-specific CD4+ and CD8+ T cell immune responses, together with an increase in the memory phase of levels of antibody against Env. Thus, the selective deletion of the N2L viral immunomodulatory gene is important for the optimization of MVA vectors as HIV-1 vaccines.
PMCID: PMC3957918  PMID: 24390336
22.  Safety, Immunogenicity, and Surrogate Markers of Clinical Efficacy for Modified Vaccinia Ankara as a Smallpox Vaccine in HIV-Infected Subjects 
The Journal of Infectious Diseases  2012;207(5):749-758.
Background. Human immunodeficiency virus (HIV)–infected persons are at higher risk for serious complications associated with traditional smallpox vaccines. Alternative smallpox vaccines with an improved safety profile would address this unmet medical need.
Methods. The safety and immunogenicity of modified vaccinia Ankara (MVA) was assessed in 91 HIV-infected adult subjects (CD4+ T-cell counts, ≥350 cells/mm3) and 60 uninfected volunteers. The primary objectives were to evaluate the safety of MVA and immunogenicity in HIV-infected and uninfected subjects. As a measure of the potential efficacy of MVA, the ability to boost the memory response in people previously vaccinated against smallpox was evaluated by the inclusion of vaccinia-experienced HIV-infected and HIV-uninfected subjects.
Results. MVA was well tolerated and immunogenic in all subjects. Antibody responses were comparable between uninfected and HIV-infected populations, with only 1 significantly lower total antibody titer at 2 weeks after the second vaccination, while no significant differences were observed for neutralizing antibodies. MVA rapidly boosted the antibody responses in vaccinia-experienced subjects, supporting the efficacy of MVA against variola.
Conclusions. MVA is a promising candidate as a safer smallpox vaccine, even for immunocompromised individuals, a group for whom current smallpox vaccines have an unacceptable safety profile.
Clinical Trials Registration. NCT00189904.
PMCID: PMC3611764  PMID: 23225902
Smallpox; vaccine; HIV; MVA
23.  Preclinical Studies of a Modified Vaccinia Virus Ankara-Based HIV Candidate Vaccine: Antigen Presentation and Antiviral Effect▿  
Journal of Virology  2010;84(10):5314-5328.
Poxvirus-based human immunodeficiency virus (HIV) vaccine candidates are currently under evaluation in preclinical and clinical trials. Modified vaccinia virus Ankara (MVA) vectors have excellent safety and immunogenicity records, but their behavior in human cell cultures remains only partly characterized. We studied here various virological and immunological aspects of the interactions of MVA-HIV, a vaccine candidate developed by the French National Agency for AIDS Research (ANRS), with primary human cells. We report that MVA-HIV infects and drives Gag expression in primary macrophages, dendritic cells (DCs), and epithelial and muscle cells. MVA-HIV-infected DCs matured, efficiently presented Gag, Pol, and Nef antigens, and activated HIV-specific cytotoxic T lymphocytes (CTLs). As expected with this type of vector, infection was cytopathic and led to DC apoptosis. Coculture of MVA-HIV-infected epithelial cells or myotubes with DCs promoted efficient Gag antigen major histocompatibility complex class I (MHC-I) cross-presentation without inducing direct infection and death of DCs. Antigen-presenting cells (APCs) infected with MVA-HIV also activated HIV-specific CD4+ T cells. Moreover, exposure of DCs to MVA-HIV or to MVA-HIV-infected myotubes induced type I interferon (IFN) production and inhibited subsequent HIV replication and transfer to lymphocytes. Altogether, these results show that MVA-HIV promotes efficient MHC-I and MHC-II presentation of HIV antigens by APCs without facilitating HIV replication. Deciphering the immune responses to MVA in culture experiments will help in the design of innovative vaccine strategies.
PMCID: PMC2863849  PMID: 20219934
24.  Pre-Clinical Development of BCG.HIVACAT, an Antibiotic-Free Selection Strain, for HIV-TB Pediatric Vaccine Vectored by Lysine Auxotroph of BCG 
PLoS ONE  2012;7(8):e42559.
In the past, we proposed to develop a heterologous recombinant BCG prime-recombinant modified vaccinia virus Ankara (MVA) boost dual pediatric vaccine platform against transmission of breast milk HIV-1 and Mycobacterium tuberculosis (Mtb). In this study, we assembled an E. coli-mycobacterial shuttle plasmid pJH222.HIVACAT expressing HIV-1 clade A immunogen HIVA. This shuttle vector employs an antibiotic resistance-free mechanism based on Operator-Repressor Titration (ORT) system for plasmid selection and maintenance in E. coli and lysine complementation in mycobacteria. This shuttle plasmid was electroporated into parental lysine auxotroph (safer) strain of BCG to generate vaccine BCG.HIVACAT. All procedures complied with Good Laboratory Practices (GLPs). We demonstrated that the episomal plasmid pJH222.HIVACAT was stable in vivo over a 20-week period, and genetically and phenotypically characterized the BCG.HIVACAT vaccine strain. The BCG.HIVACAT vaccine in combination with MVA.HIVA induced HIV-1- and Mtb-specific interferon γ-producing T-cell responses in newborn and adult BALB/c mice. On the other hand, when adult mice were primed with BCG.HIVACAT and boosted with MVA.HIVA.85A, HIV-1-specific CD8+ T-cells producing IFN-γ, TNF-α, IL-2 and CD107a were induced. To assess the biosafety profile of BCG.HIVACAT-MVA.HIVA regimen, body mass loss of newborn mice was monitored regularly throughout the vaccination experiment and no difference was observed between the vaccinated and naïve groups of animals. Thus, we demonstrated T-cell immunogenicity of a novel, safer, GLP-compatible BCG-vectored vaccine using prototype immunogen HIVA. Second generation immunogens derived from HIV-1 as well as other major pediatric pathogens can be constructed in a similar fashion to prime protective responses soon after birth.
PMCID: PMC3424164  PMID: 22927933
25.  Safety and Immunogenicity of DNA and MVA HIV-1 Subtype C Vaccine Prime-Boost Regimens: A Phase I Randomised Trial in HIV-Uninfected Indian Volunteers 
PLoS ONE  2013;8(2):e55831.
Study Design
A randomized, double-blind, placebo controlled phase I trial.
The trial was conducted in 32 HIV-uninfected healthy volunteers to assess the safety and immunogenicity of prime-boost vaccination regimens with either 2 doses of ADVAX, a DNA vaccine containing Chinese HIV-1 subtype C env gp160, gag, pol and nef/tat genes, as a prime and 2 doses of TBC-M4, a recombinant MVA encoding Indian HIV-1 subtype C env gp160, gag, RT, rev, tat, and nef genes, as a boost in Group A or 3 doses of TBC-M4 alone in Group B participants. Out of 16 participants in each group, 12 received vaccine candidates and 4 received placebos.
Both vaccine regimens were found to be generally safe and well tolerated. The breadth of anti-HIV binding antibodies and the titres of anti-HIV neutralizing antibodies were significantly higher (p<0.05) in Group B volunteers at 14 days post last vaccination. Neutralizing antibodies were detected mainly against Tier-1 subtype B and C viruses. HIV-specific IFN-γ ELISPOT responses were directed mostly to Env and Gag proteins. Although the IFN-γ ELISPOT responses were infrequent after ADVAX vaccinations, the response rate was significantly higher in group A after 1st and 2nd MVA doses as compared to the responses in group B volunteers. However, the priming effect was short lasting leading to no difference in the frequency, breadth and magnitude of IFN-γELISPOT responses between the groups at 3, 6 and 9 months post-last vaccination.
Although DNA priming resulted in enhancement of immune responses after 1st MVA boosting, the overall DNA prime MVA boost was not found to be immunologically superior to homologous MVA boosting.
Trial Registration
Clinical Trial Registry CTRI/2009/091/000051
PMCID: PMC3572184  PMID: 23418465

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