Prime-boost Combinations Research Articles

Biomedical Strategies for Human Immunodeficiency Virus (HIV) Prevention? A New Paradigm

This article presents recent developments in biomedical interventions for prevention of sexual transmission of the human immunodeficiency virus (HIV) infection. A review of results from randomised clinical trials on the use of antiretroviral (ARV) medications and other biomedical methods to prevent the transmission and acquisition of HIV infection. Pre-exposure prophylaxis (PrEP) refers to the provision of ARV medications to uninfected persons at high risk of HIV infection either in the form of topical agents, e.g. vaginal microbicide gels, or orally administered tablets. The Caprissa study demonstrated the efficacy of vaginal microbicides, the Vaginal and Oral Interventions to Control the Epidemic (VOICE) study however was not able to confirm these results. Oral PrEP was found to be efficacious in the iPrEx study on men who have sex with men (MSM), and among heterosexual couples in the Partners-PrEP and the TDF2 studies in Africa. The HPTN 052 trial demonstrated that the provision of early ARV treatment was able to prevent transmission of HIV by 92% compared with delayed treatment. This has led to enthusiasm to roll out treatment as prevention (TasP) programmes. Encouraging results from studies on male circumcision to prevent HIV acquisition have resulted in several implementation projects in Africa. Another encouraging result has been the success, albeit modest, of the prime-boost combination RV144 vaccine trial in Thailand. New advances in prevention strategies are urgently needed to slow down the HIV pandemic. Recent developments particularly in the form of PrEP and TasP have given new hope that we will be able to achieve this goal.

Human immunodeficiency virus vaccine trials.

More than 2 million AIDS-related deaths occurred globally in 2008, and more than 33 million people are living with HIV/AIDS. Despite promising advances in prevention, an estimated 2.7 million new HIV infections occurred in that year, so that for every two patients placed on combination antiretroviral treatment, five people became infected. The pandemic poses a formidable challenge to the development, progress, and stability of global society 30 years after it was recognized. Experimental preventive HIV-1 vaccines have been administered to more than 44,000 human volunteers in more than 187 separate trials since 1987. Only five candidate vaccine strategies have been advanced to efficacy testing. The recombinant glycoprotein (rgp)120 subunit vaccines, AIDSVAX B/B and AIDSVAX B/E, and the Merck Adenovirus serotype (Ad)5 viral-vector expressing HIV-1 Gag, Pol, and Nef failed to show a reduction in infection rate or lowering of postinfection viral set point. Most recently, a phase III trial that tested a heterologous prime-boost vaccine combination of ALVAC-HIV vCP1521 and bivalent rgp120 (AIDSVAX B/E) showed 31% efficacy in protection from infection among community-risk Thai participants. A fifth efficacy trial testing a DNA/recombinant(r) Ad5 prime-boost combination is currently under way. We review the clinical trials of HIV vaccines that have provided insight into human immunogenicity or efficacy in preventing HIV-1 infection.

Heterologous Prime-Boost Regimens Using rAd35 and rMVA Vectors Elicit Stronger Cellular Immune Responses to HIV Proteins Than Homologous Regimens

We characterized prime-boost vaccine regimens using heterologous and homologous vector and gene inserts. Heterologous regimens offer a promising approach that focuses the cell-mediated immune response on the insert and away from vector-dominated responses. Ad35-GRIN/ENV (Ad35-GE) vaccine is comprised of two vectors containing sequences from HIV-1 subtype A gag, rt, int, nef (Ad35-GRIN) and env (Ad35-ENV). MVA-CMDR (MVA-C), MVA-KEA (MVA-K) and MVA-TZC (MVA-T) vaccines contain gag, env and pol genes from HIV-1 subtypes CRF01_AE, A and C, respectively. Balb/c mice were immunized with different heterologous and homologous vector and insert prime-boost combinations. HIV and vector-specific immune responses were quantified post-boost vaccination. Gag-specific IFN-γ ELISPOT, intracellular cytokine staining (ICS) (CD107a, IFN-γ, TNF-α and IL-2), pentamer staining and T-cell phenotyping were used to differentiate responses to inserts and vectors. Ad35-GE prime followed by boost with any of the recombinant MVA constructs (rMVA) induced CD8+ Gag-specific responses superior to Ad35-GE-Ad35-GE or rMVA-rMVA prime-boost combinations. Notably, there was a shift toward insert-focus responses using heterologous vector prime-boost regimens. Gag-specific central and effector memory T cells were generated more rapidly and in greater numbers in the heterologous compared to the homologous prime-boost regimens. These results suggest that heterologous prime-boost vaccination regimens enhance immunity by increasing the magnitude, onset and multifunctionality of the insert-specific cell-mediated immune response compared to homologous vaccination regimens. This study supports the rationale for testing heterologous prime-boost regimens in humans.

HLA class II restriction of HIV-1 clade-specific neutralizing antibody responses in ethnic Thai recipients of the RV144 prime-boost vaccine combination of ALVAC-HIV and AIDSVAX® B/E

Immune responses to vaccines may be influenced or associated with allelic variants of host genes such as those encoding human leucocyte antigens (HLA). We have molecularly determined the HLA class II DR and DQ gene, allele and haploype profiles in HIV-1 negative ethnic Thai recipients of an HIV-1 prime boost vaccine regimen, designed to induce neutralizing antibody (NAb) responses to HIV-1 CRF01_AE. Non-response to vaccine associated with DRB1*11 (3/32 responders vs. 7/13 non-responders, p(c)=0.027) and DRB1*16:02 (0/32 responders vs. 4/13 non-responders, p(c)=0.078) alleles. Furthermore, vaccine recipients with HLA-DQ heterodimers encoded by DQA1*05:01 and DQB1*03:01 alleles, were much less likely to produce NAb (p=0.009). These data suggest that the lack of response to a vaccine designed to induce clade-specific NAb to HIV-1 is associated with the presence of certain HLA class II alleles and heterodimers in some Southeast Asians.

HIV-DNA Priming Alters T Cell Responses to HIV-Adenovirus Vaccine Even When Responses to DNA Are Undetectable

Many candidate HIV vaccines are designed to primarily elicit T cell responses. Although repeated immunization with the same vaccine boosts Ab responses, the benefit for T cell responses is ill defined. We compared two immunization regimens that include the same recombinant adenoviral serotype 5 (rAd5) boost. Repeated homologous rAd5 immunization fails to increase T cell responses, but increases gp140 Ab responses 10-fold. DNA prime, as compared with rAd5 prime, directs long-term memory CD8(+) T cells toward a terminally differentiated effector memory phenotype with cytotoxic potential. Based on the kinetics of activated cells measured directly ex vivo, the DNA vaccination primes for both CD4(+) and CD8(+) T cells, despite the lack of detection of the latter until after the boost. These results suggest that heterologous prime-boost combinations have distinct immunological advantages over homologous prime-boosts and suggest that the effect of DNA on subsequent boosting may not be easily detectable directly after the DNA vaccination.

Newcastle Disease Virus Expressing Human Immunodeficiency Virus Type 1 Envelope Glycoprotein Induces Strong Mucosal and Serum Antibody Responses in Guinea Pigs

Human immunodeficiency virus type 1 (HIV-1) is transmitted mainly through mucosal sites. Optimum strategies to elicit both systemic and mucosal immunity are critical for the development of vaccines against HIV-1. We therefore sought to evaluate the induction of systemic and mucosal immune responses by the use of Newcastle disease virus (NDV) as a vaccine vector. We generated a recombinant NDV, designated rLaSota/gp160, expressing the gp160 envelope (Env) protein of HIV-1 from an added gene. The gp160 protein expressed by rLaSota/gp160 virus was detected on an infected cell surface and was incorporated into the NDV virion. Biochemical studies showed that gp160 present in infected cells and in the virion formed a higher-order oligomer that retained recognition by conformationally sensitive monoclonal antibodies. Expression of gp160 did not increase the virulence of recombinant NDV (rNDV) strain LaSota. Guinea pigs were administered rLaSota/gp160 via the intranasal (i.n.) or intramuscular (i.m.) route in different prime-boost combinations. Systemic and mucosal antibody responses specific to the HIV-1 envelope protein were assessed in serum and vaginal washes, respectively. Two or three immunizations via the i.n. or i.m. route induced a more potent systemic and mucosal immune response than a single immunization by either route. Priming by the i.n. route was more immunogenic than by the i.m. route, and the same was true for the boosts. Furthermore, immunization with rLaSota/gp160 by any route or combination of routes induced a Th1-type response, as reflected by the induction of stronger antigen-specific IgG2a than IgG1 antibody responses. Additionally, i.n. immunization elicited a stronger neutralizing serum antibody response to laboratory-adapted HIV-1 strain MN.3. These data illustrate that it is feasible to use NDV as a vaccine vector to elicit potent humoral and mucosal responses to the HIV-1 envelope protein.

Modeling the impact of RV144-like vaccines on HIV transmission

Some 30 years after the public first became aware of AIDS, the need for a safe, effective, and affordable HIV vaccine remains compelling [1]. To date, the road to an HIV vaccine has been rocky, marked by the well-publicized failures of the first two candidates to reach large population trials. The first, a recombinant gp120 AIDSVAX® B/E vaccine, proved ineffective [2, 3]. The second, a Merck recombinant adenovirus 5 gag/pol/nef HIV-1 vaccine targeting cell-mediated immunity in the STEP trial, actually increased the risk of HIV acquisition among vaccinees relative to placebo recipients [4]. Then, just as vaccine developers were returning to their drawing boards [5], the roller-coaster swung up again. On 20 October 2009, results of RV144 – a large, long duration, expensive (~120 million US$), community Phase III trial in Thailand evaluating a combination of two vaccines, ALVAC® HIV vaccine (a 4-dose prime) and the aforementioned AIDSVAX® B/E vaccine (a 2-dose boost) – were announced at the AIDS Vaccine 2009 Conference in Paris, France. There were 51 infections in 26,507 vaccinated person-years versus 74 in 26,478 unvaccinated person-years (p=0.04). Excluding 7 trial participants who were infected before vaccination, this prime-boost combination reduced the risk of HIV infection by 31.2% (95% CI, 1.1 to 51.2) overall compared to placebo [6].

A novel candidate HIV vaccine vector based on the replication deficient Capripoxvirus, Lumpy skin disease virus (LSDV)

BackgroundThe Capripoxvirus, Lumpy skin disease virus (LSDV) has a restricted host-range and is being investigated as a novel HIV-1 vaccine vector. LSDV does not complete its replication cycle in non-ruminant hosts.MethodsThe safety of LSDV was tested at doses of 104 and 106 plaque forming units in two strains of immunocompromised mice, namely RAG mice and CD4 T cell knockout mice. LSDV expressing HIV-1 subtype C Gag, reverse transcriptase (RT), Tat and Nef as a polyprotein (Grttn), (rLSDV-grttn), was constructed. The immunogenicity of rLSDV-grttn was tested in homologous prime-boost regimens as well as heterologous prime-boost regimes in combination with a DNA vaccine (pVRC-grttn) or modified vaccinia Ankara vaccine (rMVA-grttn) both expressing Grttn.ResultsSafety was demonstrated in two strains of immunocompromised mice.In the immunogenicity experiments mice developed high magnitudes of HIV-specific cells producing IFN-gamma and IL-2. A comparison of rLSDV-grttn and rMVA-grttn to boost a DNA vaccine (pVRC-grttn) indicated a DNA prime and rLSDV-grttn boost induced a 2 fold (p < 0.01) lower cumulative frequency of Gag- and RT-specific IFN-γ CD8 and CD4 cells than a boost with rMVA-grttn. However, the HIV-specific cells induced by the DNA vaccine prime rLSDV-grttn boost produced greater than 3 fold (p < 0.01) more IFN- gamma than the HIV-specific cells induced by the DNA vaccine prime rMVA-grttn boost. A boost of HIV-specific CD4 cells producing IL-2 was only achieved with the DNA vaccine prime and rLSDV-grttn boost. Heterologous prime-boost combinations of rLSDV-grttn and rMVA-grttn induced similar cumulative frequencies of IFN- gamma producing Gag- and RT-specific CD8 and CD4 cells. A significant difference (p < 0.01) between the regimens was the higher capacity (2.1 fold) of Gag-and RT-specific CD4 cells to produce IFN-γ with a rMVA-grttn prime - rLSDV-grttn boost. This regimen also induced a 1.5 fold higher (p < 0.05) frequency of Gag- and RT-specific CD4 cells producing IL-2.ConclusionsLSDV was demonstrated to be non-pathogenic in immunocompromised mice. The rLSDV-grttn vaccine was immunogenic in mice particularly in prime-boost regimens. The data suggests that this novel vaccine may be useful for enhancing, in particular, HIV-specific CD4 IFN- gamma and IL-2 responses induced by a priming vaccine.

Single-cell gene-expression profiling reveals qualitatively distinct CD8 T cells elicited by different gene-based vaccines

CD8 T cells play a key role in mediating protective immunity against selected pathogens after vaccination. Understanding the mechanism of this protection is dependent upon definition of the heterogeneity and complexity of cellular immune responses generated by different vaccines. Here, we identify previously unrecognized subsets of CD8 T cells based upon analysis of gene-expression patterns within single cells and show that they are differentially induced by different vaccines. Three prime-boost vector combinations encoding HIV Env stimulated antigen-specific CD8 T-cell populations of similar magnitude, phenotype, and functionality. Remarkably, however, analysis of single-cell gene-expression profiles enabled discrimination of a majority of central memory (CM) and effector memory (EM) CD8 T cells elicited by the three vaccines. Subsets of T cells could be defined based on their expression of Eomes, Cxcr3, and Ccr7, or Klrk1, Klrg1, and Ccr5 in CM and EM cells, respectively. Of CM cells elicited by DNA prime-recombinant adenoviral (rAd) boost vectors, 67% were Eomes(-) Ccr7(+) Cxcr3(-), in contrast to only 7% and 2% stimulated by rAd5-rAd5 or rAd-LCMV, respectively. Of EM cells elicited by DNA-rAd, 74% were Klrk1(-) Klrg1(-)Ccr5(-) compared with only 26% and 20% for rAd5-rAd5 or rAd5-LCMV. Definition by single-cell gene profiling of specific CM and EM CD8 T-cell subsets that are differentially induced by different gene-based vaccines will facilitate the design and evaluation of vaccines, as well as enable our understanding of mechanisms of protective immunity.

The future of mucosal HIV vaccines

Approximately 33 million people live with the human immunodeficiency virus (HIV) and 2.6 million new infections are acquired each yea1. The development of an effective HIV vaccine that induces robust mucosal immunity represents a major global public health challenge. Large human efficacy trials of simple antibody-based and cytotoxic T cell-based vaccines have failed to provide any protection. The recent RV144 HIV vaccine efficacy trial in Thailand using a prime-boost combination of vaccines, however, showed modest efficacy (31%, p=0.04 on the primary analysis). Although the efficacy was marginal, the study has provided considerable hope that a vaccine to prevent infection by HIV may be feasible.

HIV/AIDS vaccine development: are we walking out from the dark?

The need for AIDS vaccine has been emphasized by the increase of HIV-1 prevalence in sexual transmission which bridges the spreading of HIV-1 from high-risk population to other populations. After more than two-decade intensive effort on the AIDS vaccine development it remains elusive whether and how an effective vaccine will be achieved. Recent data released from a phase III trial in Thailand showed a partial protection might be accomplishable by the "prime-boost" combination of two vaccines: ALVAC® HIV vaccine (the prime) and AIDSVAX® B/E vaccine (the boost) This unprecedented large clinical trial observed that the prime-boost combination lowered the rate of HIV infection by 31.2% compared to placebo based on the modified intent-to-treat population (n=51 vs. n=74 respectively; P=0.04). However debating on the efficacy interpretation of this trial arose among field scientists. Furthermore how to improve the efficacy will become the most important question to be tackled. Here we reviewed the recent publications and summarized the major progress achieved.

Combination prevention: a deeper understanding of effective HIV prevention

Evidence-informed and human rights-based combination prevention combines behavioural, biomedical, and structural interventions to address both the immediate risks and underlying causes of vulnerability to HIV infection, and the pathways that link them. Because these are context-specific, no single prescription or standard package will apply universally. Anchored in 'know your epidemic' estimates of where the next 1000 infections will occur and 'know your response' analyses of resource allocation and programming gaps, combination prevention strategies seek to realign programme priorities for maximum effect to reduce epidemic reproductive rates at local, regional, and national levels. Effective prevention means tailoring programmes to local epidemics and ensuring that components are delivered with the intensity, quality, and scale necessary to achieve intended effects. Structural interventions, addressing the social, economic, cultural, and legal constraints that create HIV risk environments and undermine the agency of individuals to protect themselves and others, are also public goods in their own right. Applying the principles of combination prevention systematically and consistently in HIV programme planning, with due attention to context, can increase HIV programme effectiveness. Better outcome and impact measurement using multiple methods and data triangulation can build the evidence base on synergies between the components of combination prevention at individual, group, and societal levels, facilitating iterative knowledge translation within and among programmes.

An Effective HIV Vaccine: A Combination of Humoral and Cellular Immunity?

The development of a safe and effective HIV vaccine remains the best hope to control the global HIV epidemic. So far, the different strategies tried for vaccine development have led to disappointing results. The first attempted strategy involved trying to raise neutralizing antibodies to inactivate the virus and prevent infection. Both of Vaxgen's VAX004 and VAX003 phase 3 trials made use of this approach but ultimately failed. Given the difficulties encountered, the focus then shifted to the cell mediated arm of the immune system, the T lymphocytes. However, the phase 2 STEP study, which was aimed to stimulate cell-mediated immunity, was halted in 2007 because it failed to prevent infection and there was an increased incidence of HIV infection in vaccinated individuals. Many researchers now believe that vaccine candidates need to induce both sustained broadly neutralizing antibodies and a strong cell-mediated response. Therefore, attention is now focused on the prime-boost approach: a DNA or vector vaccine to elicit cytotoxic T cells that destroy infected cells followed by a subunit vaccine to induce neutralizing antibodies. RV144, the largest ever HIV vaccine trial, used a prime-boost combination vaccine, which was shown to be safe and modestly effective. The ongoing RV152 study will provide more information on the modest degree of efficacy of the RV144 vaccine with results expected in 2013. Finally, the ongoing HVTN 505 trial also makes use of the prime-boost strategy and is expected to provide a better understanding of T-cell-based vaccines. In this review, we discuss the results of all the above-mentioned trials and consider whether an HIV vaccine needs to induce both humoral and cellular immunity to be effective.

Application of Electroporation in DNA Vaccination Protocols

Vaccination is historically one of the most important methods for preventing infectious diseases in humans and animals. Due to recent advances in understanding the biology of the immune system, a more rational design of vaccines and vaccination strategies such as those based on gene transfer have been proposed. In particular, naked DNA vaccination is emerging as a promising approach for introducing foreign antigens into the host, inducing protective immunity against infectious diseases and malignant tumours. Plasmid DNA vaccines offer several advantages in comparison to traditional vaccines such as safety, tolerability and feasibility in manufacture. Nevertheless, because of their poor immunogenicity, plasmid DNA vaccines need further implementation. Recent data suggest electroporation as useful strategy to improve DNA-based vaccination protocols, being able to stimulate both the humoural and cellular immune responses. In pre-clinical trials, electroporation is successfully used in prime-boost combination protocols and its efficacy and tolerability has been demonstrated in Phase I clinical trials. Since these initial results appear promising, in the next future we will assist to further developments of naked DNA vaccination associated to the electroporation technology. This approach not only provides the basis for human studies but also a practical application to veterinary medicine.

Development of a Skin Test for Bovine Tuberculosis for Differentiating Infected from Vaccinated Animals

The tuberculin skin test has been used for the diagnosis of bovine and human tuberculosis (TB) for over a hundred years. However, the specificity of the test is compromised by vaccination with the Mycobacterium bovis-derived vaccine strain bacille Calmette-Guérin (BCG). Since current promising vaccines against bovine TB are based on heterologous prime-boost combinations that include BCG, there is a need for diagnostic tests for differentiating infected from vaccinated animals (DIVA). The application of antigens such as ESAT-6 and CFP-10 for DIVA has so far been realized largely through their application in the blood-based gamma interferon release assay. In the current study, we have reassessed the potential of such antigens as skin test reagents for DIVA in cattle. A cocktail of the Mycobacterium tuberculosis complex recombinant protein antigens ESAT-6, CFP-10, MPB70, and MPB83 elicited delayed-type hypersensitivity (DTH) skin test responses in 78% of naturally infected tuberculin-positive cattle. Importantly, this cocktail induced no skin responses in BCG-vaccinated cattle despite them being sensitized for strong tuberculin responses. Further optimization of skin test antigen combinations identified that the inclusion of Rv3615c (Mb3645c) enhanced skin test sensitivity in naturally infected cattle without compromising specificity. In addition, we demonstrate for the first time the utility of synthetic peptides as promising skin test antigens for bovine TB for DIVA. Our data provide a promising basis for the future development of skin tests for DIVA with practical relevance for TB diagnosis in both veterinary and clinical settings.

When the presumption of innocence is not beneficial: periodic presumptive treatment for STIs and HIV in female sex workers

The recent announcement that a prime-boost combination of two HIV vaccine candidates had a partial protective efficacy of around 31% in phase III clinical trials in Thailand is encouraging,1 2 but for the foreseeable future the prevention of HIV acquisition will continue to require a multifactorial response.3 In resource-poor countries where heterosexual transmission is the dominant mode of infection, the promotion of evidence-based behavioural and biomedical prevention strategies that effectively reach vulnerable individuals most at risk of HIV and sexually transmitted infections are paramount. Female sex workers (FSWs) and their clients may represent a significant source of new HIV infections, particularly in the early stages of the epidemic.4 5 Although 100% condom usage is the gold standard for HIV and STI risk reduction for FSWs and their clients, condoms are not always available, nor are they always used, due to women's limited ability to negotiate safer sexual practices in commercial or transactional relationships.6 Sexually transmitted infections (STI) such as Neisseria gonorrhoeae (Ng) and Chlamydia trachomatis (Ct) can increase cervico-vaginal HIV shedding in women, while Ng results in greater shedding in the semen of men infected with HIV.7 This can lead to a higher likelihood of HIV transmission with an RR of about 3 for a number of STIs in both …

The successful immune response against hepatitis C nonstructural protein 5A (NS5A) requires heterologous DNA/protein immunization

The aim of this study was to evaluate the immunogenicity of NS5A protein of human hepatitis C virus (HCV) when delivered as naked DNA (NS5A DNA), or recombinant protein (rNS5A). DBA/2J mice received NS5A DNA, rNS5A, or NS5A DNA/rNS5A in different prime-boost combinations with a peptidoglycan Immunomax ®. The weakest response was induced after rNS5A prime and NS5A DNA boost; rNS5A alone induced an immune response with a strong Th2-component; and NS5A DNA alone, a relatively weak secretion of IL-2 and IFN-γ. The most efficient was co-injection of NS5A DNA and rNS5A, which induced a significant increase in CD4 + and CD8 + T-cell counts, anti-NS5A antibodies, specific T-cell proliferation, and proinflammatory cytokine production in vitro against a broad spectrum of NS5A epitopes. Administration of the mixture of adjuvanted DNA and protein immunogens can be selected as the best regimen for further preclinical HCV-vaccine trials.

Prime-Boost Vaccination with Recombinant Mumps Virus and Recombinant Vesicular Stomatitis Virus Vectors Elicits an Enhanced Human Immunodeficiency Virus Type 1 Gag-Specific Cellular Immune Response in Rhesus Macaques

Intramuscular inoculation of rhesus macaques with one or more doses of recombinant vesicular stomatitis virus (rVSV) expressing human immunodeficiency virus type 1 (HIV-1) Gag (rVSVgag) typically elicits peak cellular immune responses of 500 to 1,000 gamma interferon (IFN-gamma) enzyme-linked immunospots (ELISPOTS)/10(6) peripheral blood lymphocytes (PBL). Here, we describe the generation of a novel recombinant mumps virus (rMuV) expressing HIV-1 Gag (rMuVgag) and measure the Gag-specific cellular immune responses detected in rhesus macaques following vaccination with a highly attenuated form of rVSV expressing HIV-1 Gag (rVSVN4CT1gag1) and rMuVgag in various prime-boost combinations. Notably, peak Gag-specific cellular immune responses of 3,000 to 3,500 ELISPOTS/10(6) PBL were detected in macaques that were primed with rMuVgag and boosted with rVSVN4CT1gag1. Lower peak cellular immune responses were detected in macaques that were primed with rVSVN4CT1gag1 and boosted with rMuVgag, although longer-term gag-specific responses appeared to remain higher in this group of macaques. These findings indicate that rMuVgag may significantly enhance Gag-specific cellular immune responses when administered with rVSVN4CT1gag1 in heterologous prime-boost regimens.

Comparison of multiple vaccine vectors in a single heterologous prime-boost trial

The prevention of infectious disease via prophylactic immunization is a mainstay of global public health efforts. Vaccine design would be facilitated by a better understanding of the type and durability of immune responses generated by different vaccine vectors. We report here the results of a comparative immunogenicity trial of six different vaccine vectors expressing the same insert antigen, cowpox virus B5 (CPXV-B5). Of those vectors tested, recombinant adenovirus (rAd5) was the most immunogenic, inducing the highest titer anti-B5 antibodies and conferring protection from sublethal vaccinia virus challenge in mice after a single immunization. We tested select heterologous prime-boost combinations and identified recombinant vesicular stomatitis virus (rVSV) and recombinant Venezuelan equine encephalitis virus replicons (VRP) as the most synergistic regimen. Comparative data such as those presented here are critical to efforts to generate protective vaccines for emerging infectious diseases as well as for biothreat agents.

Demand Forecasting for Preventive??AIDS Vaccines

An AIDS vaccine could play a very significant role in reversing the HIV pandemic, saving millions of lives. For a vaccine to have such an impact, it must be widely available and adopted and taken up rapidly in the countries most affected. A demand-forecasting model provides a valuable tool that can guide R&D spending decisions and identify policy actions to help achieve these goals. To identify the key determinants of vaccine demand, model global adoption and uptake dynamics, estimate potential demand and revenues associated with future preventive AIDS vaccines, and to conduct sensitivity analyses to assess the impact of each parameter on demand. A discrete, deterministic, linear, predictive mathematical model based on stratified population averages with a 30-year time horizon was developed to assess scenarios of future demand. This forecasting model was used to explore the effects of vaccine characteristics and a variety of regulatory, political, financial and health service factors on future demand and revenues. The intervention modelled was a preventive AIDS vaccine (efficacy: 30-90%; duration of protection: 3-5 years; in a two-dose prime-boost combination). The main outcome measure was the number of complete courses of vaccine administered. The model suggests that demand for a preventive AIDS vaccine with a medium efficacy (50%) and duration of protection (3 years) would average 68 million courses annually over a 30-year period. Under different scenarios, demand would peak at 38-152 million courses annually. On the basis of tiered pricing across public and private markets ($US2-100 per dose), these levels of peak demand would translate into $US2.5-5.5 billion in peak annual sales revenues. Private markets and high-income countries account for small volumes but large shares of projected revenues, while low-income countries account for large volumes and more modest, but still significant, sales revenues. Vaccinations to 'catch-up' those who are missed or not eligible for routine annual programmes (whether adolescent or high-risk populations) would account for 20-35% of cumulative vaccination courses across all scenarios. Demand was found to be sensitive to vaccine efficacy, duration of protection and price. Efforts to expedite regulatory review processes, improve immunization infrastructure and reduce political constraints could increase demand for an AIDS vaccine by 40 million additional courses a year compared with the medium efficacy (baseline) vaccine forecast. Our model can provide vaccine developers with credible estimates of market potential for an AIDS vaccine, and with a tool that can be used to improve forecasts over time as AIDS vaccine science progresses. It can also help governments to identify and pursue those policies that could best strengthen demand and uptake of a safe and effective preventive AIDS vaccine.