The quest for a T cell-based immune correlate of protection against HIV: a story of trials and errors

Even before the partial success of a preventive HIV vaccine in a recent Phase III clinical trial, there had been an active research effort to determine one or more immune correlates of protection for HIV infection. This effort has been hampered by the lack of natural protective immunity against HIV. As a result, most of the studies have focused on long-term non-progressive infection or other clinical situations, none of which fully recapitulates protective immunity against HIV. Although this effort has been successful in defining characteristics of T cells in acute and non-progressive HIV infection, and has therefore greatly expanded our knowledge of the immunopathogenesis of AIDS, its success in defining immune correlates of protection is less clear. In this Opinion article we offer a perspective on how successful this effort has been in defining immune correlates of protection that have been, or will be, of use in the development of an HIV vaccine. Our view is that investing in an iterative approach to human vaccine efficacy trials of sufficient size and sampling frequency will improve the likelihood that an immune correlate of vaccine protection will be defined.     

Virus-like particles: designing an effective AIDS vaccine

Viruses that infect eukaryotic organisms have the unique characteristic of self-assembling into particles. The mammalian immune system is highly attuned to recognizing and attacking these viral particles following infection. The use of particle-based immunogens, often delivered as live-attenuated viruses, has been an effective vaccination strategy for a variety of viruses. The development of an effective vaccine against the human immunodeficiency virus (HIV) has proven to be a challenge, since HIV infects cells of the immune system causing severe immunodeficiency resulting in the syndrome known as AIDS. In addition, the ability of the virus to adapt to immune pressure and reside in an integrated form in host cells presents hurdles for vaccinologists to overcome. A particle-based vaccine strategy has promise for eliciting high titer, long-lived, immune responses to a diverse number of viral epitopes against different HIV antigens. Live-attenuated viruses are effective at generating both cellular and humoral immune responses. However, while these vaccines stimulate immunity, challenged animals rarely clear the viral infection and the degree of attenuation directly correlates with protection from disease. Further, a live-attenuated vaccine has the potential to revert to a pathogenic form. Alternatively, virus-like particles (VLPs) mimic the viral particle without causing an immunodeficiency disease. VLPs are self-assembling, non-replicating, non-pathogenic particles that are similar in size and conformation to intact virions. A variety of VLPs for lentiviruses are currently in preclinical and clinical trials. This review focuses on our current status of VLP-based AIDS vaccines, regarding issues of purification and immune design for animal and clinical trials.     

Live recombinant vectors for AIDS vaccine development

Live recombinant vectors entered the AIDS vaccine field with the realization that live attenuated HIV vaccines posed too great a safety risk, and that subunit vaccines elicited antibodies which lacked the breadth or potency needed to induce sterilizing immunity. Vectored vaccines provided a means to bring the cellular arm of the immune system into play by mimicking natural viral infection. By delivering antigens within host cells, processing and presentation could occur for induction of cellular immune responses. This recombinant vector approach, either alone or combined with other strategies, has produced impressive results. Recombinants have been generated from DNA and RNA viruses and bacteria. With few exceptions, each vector poses some risk, yet each possesses unique features that make it attractive. In addition to safety, key considerations in vector selection have included previous success as a vaccine against the wild-type agent or other pathogens; ability to induce potent, persistent immune responses; ability to target mucosal inductive sites and antigen presenting cells; lack of integration into the host genome; presence of pre-existing immunity in people; ease of mucosal administration; cloning capacity; ease of engineering and production; and stability of the final product. Here we up-date the status of several live recombinant vectors that have shown good potential in pre-clinical studies. Some have progressed to human clinical trials, and others will shortly. The abundance of vectors, coupled with the complexity arising from use of combination regimens with other vaccine types and heterologous vectors, will necessitate selection of the most promising candidates for large-scale efficacy trials in people. The sooner comparative studies can be designed and implemented in which live recombinant vectors containing the same inserted genes are evaluated head-to-head, the closer we will be to an eventual vaccine.     

Towards an AIDS vaccine: the role of nonhuman primates

Over the last 10 years, about 20 human immunodeficiency virus (HIV) vaccine candidates have been tried in humans, with disappointing results as gauged by limited immune responses or protection against infection. These difficulties suggest that a new strategy is needed to test systematically new vaccine candidates. That opportunity is now afforded by nonhuman primate models with SIV, which have been shown to provide an excellent mirror of HIV infection in humans. The recent introduction of SHIVs, chimeric viruses that carry the HIV envelope and are able to infect and cause AIDS in monkeys, also has added an important additional research tool. These models can be used to address a series of questions, including the following: (1) Can protection be provided by partial immunity or is sterilizing immunity required? (2) What are the immune parameters that best predict protection against a potentially pathogenic challenge? (3) What role does mucosal immunity play and can it be induced by practical modes of immunization? (4) Can an attenuated virus be selected that is both protective and safe? An orderly strategy for the evaluation of vaccine candidates could be adopted that would involve several phases: (a) the selection of a limited set of challenge models, ranging from very severe to mild and requiring consideration of primate species, age, route of infection, and challenge viruses; (b) the assessment of candidate vaccines using comparable virus challenges; and (c) accelerated testing in humans of any candidate vaccines that have met a 'proof of efficacy' in primates.     

The Progress on the Studies of HIV/AIDS Vaccine

人类控制HIV感染长远的目标是发展安全、有效、廉价的HIV AIDS疫苗。但经 2 0多年的努力 ,人类探索HIV AIDS疫苗之路仍在继续。分析了疫苗研究的复杂性和发展HIV AIDS疫苗过程中所面临的挑战 ,并对发展HIV AIDS疫苗的可能性从实验和临床方面进行了阐述。同时结合HIV感染的免疫应答原理对现有的各种HIV AIDS疫苗研究策略作一综述 ,并根据以往HIV AIDS疫苗研究的经验和教训提出未来疫苗的发展思路及展望。     

Overview: from the horse experimentation by Prof. Akira Fujinami to paramyosin

Professor Akira Fujinami demonstrated for the first time in the world that acquired immunity might be induced against macroparasites such as schistosomes. Since then, vaccination models have been developed using various species of animals, among which the attenuated vaccine model in the mouse has been utilized mostly to clarify immune effector mechanisms and define candidate vaccine molecules. However, further studies are necessary on immune responses to defined parasite molecules in humans, because some discrepancies in immune responses still exist between animals and humans, and apparently genetic influence should be taken into consideration in such studies on defined molecules. Despite of some limitations, vaccine trials in livestock against Schistosoma japonicum may provide useful information for development of vaccines against the other human infections caused by S. mansoni or S. haematobium. In this overview, studies carried out mainly by Japanese investigators towards vaccine development will be described.     

Synergism/complementarity of recombinant adenoviral vectors and other vaccination platforms during induction of protective immunity against malaria

The lack of immunogenicity of most malaria antigens and the complex immune responses required for achieving protective immunity against this infectious disease have traditionally hampered the development of an efficient human malaria vaccine. The current boom in development of recombinant viral vectors and their use in prime-boost protocols that result in enhanced immune outcomes have increased the number of malaria vaccine candidates that access pre-clinical and clinical trials. In the frontline, adenoviruses and poxviruses seem to be giving the best immunization results in experimental animals and their mutual combination, or their combination with recombinant proteins (formulated in adjuvants and given in sequence or being given as protein/virus admixtures), has been shown to reach unprecedented levels of anti-malaria immunity that predictably will be somehow reproduced in the human setting. However, all this optimism was previously seen in the malaria vaccine development field without many real applicable results to date. We describe here the current state-of-the-art in the field of recombinant adenovirus research for malaria vaccine development, in particular referring to their use in combination with other immunogens in heterologous prime-boost protocols, while trying to simultaneously show our contributions and point of view on this subject.     

Structure and Dynamics of the Native HIV-1 Env Trimer

HIV-1/AIDS remains one of the worst pandemics in human history. Despite tremendous efforts, no effective vaccine has been found. Recent reports give new insights into the structure and dynamics of the HIV-1 Env trimer and renew hopes that a better understanding of Env will translate into new vaccine candidates and more-effective antiretroviral therapies.     

Parasitic infection and the polarized Th2 immune response can alter a vaccine-induced immune response

The AIDS epidemic in the Developing World represents a major global crisis. It is imperative that we develop an effective vaccine. Vaccines are economically the most efficient means of controlling viral infections. However, the development of a vaccine against HIV-1 has been a formidable task, and in developing countries chronic parasitic infection adds another level of complexity to AIDS vaccine development. Helminthic and protozoan infections, common in developing countries, can result in a constant state of immune activation that is characterized by a dominant Th2 type of cytokine profile, high IgE levels, and eosinophilia. Such an immune profile may have an adverse impact on the efficacy of vaccines, in particular, an HIV-1 vaccine. Indeed, the CD8 cellular immune response and the corresponding Th1 type cytokines that enhance the CD8 cellular immune response are important for clearing many viral infections. It is believed that an antigen specific CD8 cellular immune response will be an important component of an HIV-1 vaccine.     

Immunogenicity of Seven New Recombinant Yellow Fever Viruses 17D Expressing Fragments of SIVmac239 Gag,Nef, and Vif in Indian Rhesus Macaques

An effective vaccine remains the best solution to stop the spread of human immunodeficiency virus (HIV). Cellular immune responses have been repeatedly associated with control of viral replication and thus may be an important element of the immune response that must be evoked by an efficacious vaccine. Recombinant viral vectors can induce potent T-cell responses. Although several viral vectors have been developed to deliver HIV genes, only a few have been advanced for clinical trials. The live-attenuated yellow fever vaccine virus 17D (YF17D) has many properties that make it an attractive vector for AIDS vaccine regimens. YF17D is well tolerated in humans and vaccination induces robust T-cell responses that persist for years. Additionally, methods to manipulate the YF17D genome have been established, enabling the generation of recombinant (r)YF17D vectors carrying genes from unrelated pathogens. Here, we report the generation of seven new rYF17D viruses expressing fragments of simian immunodeficiency virus (SIV)mac239 Gag, Nef, and Vif. Studies in Indian rhesus macaques demonstrated that these live-attenuated vectors replicated in vivo, but only elicited low levels of SIV-specific cellular responses. Boosting with recombinant Adenovirus type-5 (rAd5) vectors resulted in robust expansion of SIV-specific CD8⁺ T-cell responses, particularly those targeting Vif. Priming with rYF17D also increased the frequency of CD4⁺ cellular responses in rYF17D/rAd5-immunized macaques compared to animals that received rAd5 only. The effect of the rYF17D prime on the breadth of SIV-specific T-cell responses was limited and we also found evidence that some rYF17D vectors were more effective than others at priming SIV-specific T-cell responses. Together, our data suggest that YF17D – a clinically relevant vaccine vector – can be used to prime AIDS virus-specific T-cell responses in heterologous prime boost regimens. However, it will be important to optimize rYF17D-based vaccine regimens to ensure maximum delivery of all immunogens in a multivalent vaccine.     

Potent T cell responses induced by single DNA vaccine boosted with recombinant vaccinia vaccine

Plasmid DNA, an effective vaccine vector, can induce both cellular and humoral immune responses. However, plasmid DNA raises issues concerning potential genomic integration after injection. This issue should be considered in preclinical studies. Tiantan vaccinia virus (TV) has been most widely utilized in eradicating smallpox in China. This virus has also been considered as a successful vaccine vector against a few infectious diseases. Potent T cell responses through T-cell receptor (TCR) could be induced by three injections of the DNA prime vaccine followed by a single injection of recombinant vaccinia vaccine. To develop a safer immunization strategy, a single DNA prime followed by a single recombinant Tiantan vaccinia (rTV) AIDS vaccine was used to immunize mice. Our data demonstrated that one DNA prime/rTV boost regimen induced mature TCR activation with high functional avidity, preferential T cell Vβ receptor usage and high sensitivity to anti-CD3 antibody stimulation. No differences in T cell responses were observed among one, two or three DNA prime/rTV boost regimens. This study shows that one DNA prime/rTV boost regimen is sufficient to induce potent T cell responses against HIV.     

Animal models for the study of immunity in human filariasis

A major challenge to the development of vaccines against human lymphatic filariasis and onchocerciasis is to direct the immune response toward elimination of the early, prepathogenic larval stages and away from responses that mediate pathology. In this review, James Lok and David Abraham discuss the various animal models that have been used to investigate the pathways leading to immunity, immunological tolerance and chronic pathology in these diseases. Owing to the strict host specificities of the human-dwelling filariae, no single model serves to duplicate exactly all these aspects. Nevertheless, it has been possible to demonstrate a protective immune response invoked by and directed against incoming third-stage larvae of both lymphatic and skin-dwelling filariae. The fact that subsets of the sequelae of human filarial infection can be duplicated in animal systems should also aid in unravelling the mechanisms determining the course of infection and in ensuring that vaccine candidates do not produce an inappropriate immunopathological response. A proposed scheme for using animal models in screening candidates for a vaccine against Onchocerca volvulus is presented.     

The hope for an HIV vaccine based on induction of CD8+ T lymphocytes--a review

The only long-term and cost-effective solution to the human immunodeficiency virus (HIV) epidemic in the developing world is a vaccine that prevents individuals from becoming infected or, once infected, from passing the virus on to others. There is currently little hope for an AIDS vaccine. Conventional attempts to induce protective antibody and CD8(+) lymphocyte responses against HIV and simian immunodeficiency virus (SIV) have failed. The enormous diversity of the virus has only recently been appreciated by vaccinologists, and our assays to determine CD8(+) lymphocyte antiviral efficacy are inadequate. The central hypothesis of a CTL-based vaccine is that particularly effective CD8(+) lymphocytes directed against at least five epitopes that are derived from regions under functional and structural constraints will control replication of pathogenic SIV. This would be somewhat analogous to control of virus replication by triple drug therapy or neutralizing antibodies.     

Recombinant viruses as tools to induce protective cellular immunity against infectious diseases.

Infections by intracellular pathogens such as viruses, some bacteria and many parasites, are cleared in most cases after activation of specific T cellular immune responses that recognize foreign antigens and eliminate infected cells. Vaccines against those infectious organisms have been traditionally developed by administration of whole live attenuated or inactivated microorganisms. Nowadays, research is focused on the development of subunit vaccines, containing the most immunogenic antigens from the particular pathogen. However, when purified subunit vaccines are administered using traditional immunization protocols, the levels of cellular immunity induced are mostly low and not capable of eliciting complete protection against diseases caused by intracellular microbes. In this review, we present a promising alternative to those traditional protocols, which is the use of recombinant viruses encoding subunit vaccines as immunization tools. Recombinant viruses have several interesting features that make them extremely efficient at inducing immune responses mediated by T-lymphocytes. This cellular immunity has recently been demonstrated to be of key importance for protection against malaria and AIDS, both of which are major targets of the World Health Organization for vaccine development. Thus, this review will focus in particular on the development of new vaccination protocols against these diseases.     

Liver fluke vaccines in ruminants: strategies,progress and future opportunities

The development of a vaccine for Fasciola spp. in livestock is a challenge and would be advanced by harnessing our knowledge of acquired immune mechanisms expressed by resistant livestock against fluke infection. Antibody-dependent cell-mediated cytotoxicity directed to the surface tegument of juvenile/immature flukes is a host immune effector mechanism, suggesting that antigens on the surface of young flukes may represent prime candidates for a fluke vaccine. A Type 1 immune response shortly after fluke infection is associated with resistance to infection in resistant sheep, indicating that vaccine formulations should attempt to induce Type 1 responses to enhance vaccine efficacy. In cattle or sheep, an optimal fluke vaccine would need to reduce mean fluke burdens in a herd below the threshold of 30–54 flukes to ensure sustainable production benefits. Fluke infection intensity data suggest that vaccine efficacy of approximately 80% is required to reduce fluke burdens below this threshold in most countries. With the increased global prevalence of triclabendazole-resistant Fasciolahepatica, it may be commercially feasible in the short term to introduce a fluke vaccine of reasonable efficacy that will provide economic benefits for producers in regions where chemical control of new drug-resistant fluke infections is not viable. Commercial partnerships will be needed to fast-track new candidate vaccines using acceptable adjuvants in relevant production animals, obviating the need to evaluate vaccine antigens in rodent models.     

The HIV/AIDS vaccine candidate MVA-B administered as a single immunogen in humans triggers robust, polyfunctional, and selective effector memory T cell responses to HIV-1 antigens

Attenuated poxvirus vectors expressing human immunodeficiency virus type 1 (HIV-1) antigens are considered promising HIV/AIDS vaccine candidates. Here, we describe the nature of T cell immune responses induced in healthy volunteers participating in a phase I clinical trial in Spain after intramuscular administration of three doses of the recombinant MVA-B-expressing monomeric gp120 and the fused Gag-Pol-Nef (GPN) polyprotein of clade B. The majority (92.3%) of the volunteers immunized had a positive specific T cell response at any time postvaccination as detected by gamma interferon (IFN-γ) intracellular cytokine staining (ICS) assay. The CD4(+) T cell responses were predominantly Env directed, whereas the CD8(+) T cell responses were similarly distributed against Env, Gag, and GPN. The proportion of responders after two doses of MVA-B was similar to that obtained after the third dose of MVA-B vaccination, and the responses were sustained (84.6% at week 48). Vaccine-induced CD8(+) T cells to HIV-1 antigens after 1 year were polyfunctional and distributed mainly within the effector memory (TEM) and terminally differentiated effector memory (TEMRA) T cell populations. Antivector T cell responses were mostly induced by CD8(+) T cells, highly polyfunctional, and of TEMRA phenotype. These findings demonstrate that the poxvirus MVA-B vaccine candidate given alone is highly immunogenic, inducing broad, polyfunctional, and long-lasting CD4 and CD8 T cell responses to HIV-1 antigens, with preference for TEM. Thus, on the basis of the immune profile of MVA-B in humans, this immunogen can be considered a promising HIV/AIDS vaccine candidate.     

Clinical trials of Shigella vaccines: two steps forward and one step back on a long, hard road

More than 50 years of research has yielded numerous Shigella vaccine candidates that have exemplified both the promise of vaccine-induced prevention of shigellosis and the impediments to developing a safe and effective vaccine for widespread use, a goal that has yet to be attained. This Review discusses the most advanced strategies for Shigella vaccine development, the immune responses that are elicited following disease or vaccination, the factors that have accelerated or impeded Shigella vaccine development and our ideas for the way forward.     

Influence of glycosylation on the efficacy of an Env-based vaccine against simian immunodeficiency virus SIVmac239 in a macaque AIDS model

The envelope glycoprotein (Env) of human immunodeficiency viruses (HIVs) and simian immunodeficiency viruses (SIVs) is heavily glycosylated, and this feature has been speculated to be a reason for the insufficient immune control of these viruses by their hosts. In a macaque AIDS model, we demonstrated that quintuple deglycosylation in Env altered a pathogenic virus, SIVmac239, into a novel attenuated mutant virus (delta5G). In delta5G-infected animals, strong protective immunity against SIVmac239 was elicited. These HIV and SIV studies suggested that an understanding of the role of glycosylation is critical in defining not only the virological properties but also the immunogenicity of Env, suggesting that glycosylation in Env could be modified for the development of effective vaccines. To examine the effect of deglycosylation, we constructed prime-boost vaccines consisting of Env from SIVmac239 and delta5G and compared their immunogenicities and vaccine efficacies by challenge infection with SIVmac239. Vaccination-induced immune responses differed between the two vaccine groups. Both Env-specific cellular and humoral responses were higher in wild-type (wt)-Env-immunized animals than in delta5G Env-immunized animals. Following the challenge, viral loads in SIVmac239 Env (wt-Env)-immunized animals were significantly lower than in vector controls, with controlled viral replication in the chronic phase. Unexpectedly, viral loads in delta5G Env-immunized animals were indistinguishable from those in vector controls. This study demonstrated that the prime-boost Env vaccine was effective against homologous SIVmac239 challenge. Changes in glycosylation affected both cell-mediated and humoral immune responses and vaccine efficacy.     

Immunogenicity of a DNA prime and recombinant adenovirus boost regime significantly varies between rhesus macaques of Chinese and Indian origins

BACKGROUND: Due to an ever increasing shortage of rhesus macaques of Indian origin (InR) that have been generally used for preclinical AIDS vaccine trials in non-human primates, demand is rising for Chinese rhesus macaques (ChR). However, the immunogenicity of an AIDS vaccine candidate has not been compared in parallel in both rhesus macaque subspecies. METHODS: ChR and InR were immunized with SIV/HIV DNA and adenovirus vaccine and their immune responses to SIV and HIV evaluated. RESULTS: SIV Gag- and Env-specific T-cell responses and SIV-specific lymphoproliferative responses measured in ChR were significantly weaker than those in InR (P < 0.05). By contrast, antibody responses to SIV Env, Tat, and Nef in ChR were stronger than those in InR (P < 0.05). CONCLUSIONS: Immunogenicity of an AIDS vaccine can vary significantly depending on the geographic origin implying genetic differences of macaques. This must be considered when describing and interpreting results of such vaccine studies.     

Approaches to HIV vaccine design.

Contemporary vaccines are relying increasingly on modern biotechnology and a vaccine against the AIDS virus is expected to depend even more on new technological advances. Four basic areas of vaccine development are discussed in this context: (1) selection and preparation of candidate immunogens; (2) presentation of immunogens to the immune system; (3) pre-clinical testing of vaccine candidates; and (4) monitoring of vaccine clinical trials.