Report of the Cent Gardes HIV Vaccines Conference. Part 1: The antibody response; Fondation Mérieux Conference Center, Veyrier-du-Lac, France, 25-27 October 2015.

The 2015 Cent Gardes Conference on HIV vaccines took place on October 25-27 at the Merieux Foundation Conference Center in Veyrier du Lac, near Annecy, France. The meeting reviewed progress in the development of HIV vaccines and identified new directions of future research. The field has advanced incrementally over the past year but major progress will require additional information from new clinical trials. In this article, we review the presentations on humoral immune responses to HIV, and highlight the difficulty of eliciting broadly neutralizing antibodies by vaccination. Advances in cellular immunity for HIV prevention will be reviewed separately, in a following article.

Report of the 2014 Cent Gardes HIV Vaccine Conference-Part 2: Cell-mediated immunity, mucosal protection, and clinical trials: Fondation Mérieux Conference Center, Veyrier du Lac, France, 5-7 October, 2014.

The 2014 Cent Gardes Conference took place on October 5-7, 2014, at the Fondation Mérieux Conference Center, on the shores of the Annecy Lake and aimed to review the progress and promise of HIV vaccines. The elicitation of broadly neutralizing antibodies (bNAbs), their use in passive immunization, as well as their genetic delivery (vector immunoprophylaxis) by a recombinant Adenovirus-associated virus (AAV) vector were reviewed in a preceding article [1]. Approaches to the elicitation of long-lasting T cell or mucosal immunity were also discussed and are now reviewed here. The possibility of eliciting mucosal IgAs was discussed, since it was demonstrated that transcytosis-blocking IgAs can protect monkeys against repeated vaginal challenge with a pathogenic chimeric simian and human immunodeficiency virus (SHIV). The possibility of purging the HIV reservoirs from HIV-infected persons and developing a cure of the disease was also discussed.

Report of the 2014 Cent Gardes HIV Vaccine Conference - Part 1: Neutralizing Antibodies; Fondation Mérieux Conference Center, Veyrier du Lac, France, 5-7 October 2014.

The 2014 Cent Gardes Conference took place on October 5-7 at the Fondation Mérieux Conference Center, on the shores of the Annecy Lake. The aim of the meeting was to review progress in the field of HIV vaccines during the last two years and to explore the promising avenues of future research. The identification of broadly neutralizing antibodies (bNAbs) able to neutralize a majority of circulating HIV strains has encouraged hopes for a highly effective "universal" HIV vaccine. Analysis of B-cell maturation that leads to the production of bNAbs, however, appears extremely complex, and not easily reproduced by classical active immunization. The use of bNAbs for passive immunization is thus being explored as an alternative, either for immunotherapy or prophylaxis. Their delivery by a recombinant adenovirus-associated virus (AAV), also known as vector immunoprophylaxis, has demonstrated proof-of-concept in animal models and is now in early stage clinical trials. Other approaches were discussed at the meeting, such as eliciting long-lasting T cell or mucosal immunity. In spite of remarkable progress, the quest for an efficacious HIV vaccine remains a daunting challenge.

Recent progress in HIV vaccines inducing mucosal immune responses.

In spite of several attempts over many years at developing a HIV vaccine based on classical strategies, none has convincingly succeeded to date. As HIV is transmitted primarily by the mucosal route, particularly through sexual intercourse, understanding antiviral immunity at mucosal sites is of major importance. An ideal vaccine should elicit HIV-specific antibodies and mucosal CD8⁺ cytotoxic T-lymphocyte (CTL) as a first line of defense at a very early stage of HIV infection, before the virus can disseminate into the secondary lymphoid organs in mucosal and systemic tissues. A primary focus of HIV preventive vaccine research is therefore the induction of protective immune responses in these crucial early stages of HIV infection. Numerous approaches are being studied in the field, including building upon the recent RV144 clinical trial. In this article, we will review current strategies and briefly discuss the use of adjuvants in designing HIV vaccines that induce mucosal immune responses.

Report on the first WHO integrated meeting on development and clinical trials of influenza vaccines that induce broadly protective and long-lasting immune responses: Hong Kong SAR, China, 24-26 January 2013.

On January 24-26, 2013, the World Health Organization convened the first integrated meeting on "The development and clinical trials of vaccines that induce broadly protective and long-lasting immune responses" to review the current status of development and clinical evaluation of novel influenza vaccines as well as strategies to produce and deliver vaccines in novel ways. Special attention was given to the development of possible universal influenza vaccines. Other topics that were addressed included an update on clinical trials of pandemic and seasonal influenza vaccines in high-risk groups and vaccine safety, as well as regulatory issues.

Report of the Cent Gardes HIV Vaccine Conference: The B-cell response to HIV. Part 2: Non-neutralizing antibodies: Fondation Mérieux Conference Center, Veyrier du Lac, France 5-7 November 2012.

The Cent Gardes Conference on HIV Vaccines took place on November 5-7, 2012 at the Fondation Mérieux Conference Center, Annecy, France. The aim of the meeting was to review the B cell response to human immunodeficiency virus-1 (HIV-1) infection and immunization, from broadly neutralizing antibodies (bnAbs) to non-neutralizing antibodies (n-nAbs). This paper, Part 2 of the report, focuses on potentially protective n-nAbs. Evidence was presented that n-nAbs may effectively contribute to protection against HIV, as illustrated by the recent RV144 efficacy trial. They can either act as IgGs by mediating antibody-dependent cellular cytotoxicity (ADCC) involving Fc effector functions, or as IgAs, particularly dimeric IgA1s, which can inhibit virus transcytosis through monocellular epithelia and could play an important role in mucosal immunity.

Report of the Cent Gardes HIV Vaccine Conference: The B-cell Response to HIV. Part 1: Broadly Neutralizing Antibodies Fondation Mérieux Conference Center, Veyrier du Lac, France, 5-7 November 2012.

The Cent Gardes Conference on HIV Vaccines took place on November 5-7, 2012 at the Fondation Mérieux Conference Center, Annecy, France. The aim of the meeting was to review the B cell response to human immunodeficiency virus-1 (HIV-1) infection and immunization, from broadly neutralizing antibodies (bnAbs) to non-neutralizing antibodies (n-nAbs). The production of cross-reactive bnAbs is one of the greatest challenges in HIV-1 vaccine development. In natural HIV infection, bnAbs are observed in only a minority of infected individuals and take a few years to develop. This report presents a comprehensive review of how these Abs arise, the possible role of viral evolution, and the activation and maturation requirements of B cell lines that lead to their production. Passive immunization with bnAbs provides efficient, cross-clade protection against simian/human immunodeficiency chimeric virus (SHIV) challenges in nonhuman primates. Despite many efforts to design immunogens that elicit them by active immunization, no immunogen other than HIV itself has yet been able to elicit a bnAb response. For this reason, innovative approaches are under investigation, including their production in the body through a gene delivery approach, vector immunoprophylaxis.

HIV-1 Preventive vaccines: an attainable goal?

Despite remarkable advances in HIV treatment, responsible for the saving of thousands of lives, the design of an effective HIV vaccine able to prevent infectivity and stop the AIDS epidemic remains a priority for health care. Publication of the first partly efficacious large-scale HIV vaccine trial in Thaïland in 2009 has durably transformed the HIV vaccine landscape, bringing in new hopes that an HIV protective vaccine may be doable. New correlates of protection have been identified, new HIV broadly neutralizing antibodies are regularly reported, and the importance of T-effector memory cells in protection has definitely been demonstrated. In this review, we explore the difficulties encountered in designing an HIV vaccine, relate the long road already traveled, with its many failures, describe the main vaccine strategies currently under test, which explain the current moderate optimism in HIV vaccine research.

HIV vaccine development at the turn of the 21st century.

PURPOSE OF REVIEW: To review the status of HIV vaccine development RECENT FINDINGS: Since the discovery of HIV-1 in the early 1980s considerable effort has been exerted to develop a prophylactic vaccine, with relatively meagre results. The absence of natural immunity has proven to be a major stumbling block in identifying a mechanism of protection. However, many different animal models have contributed to our knowledge of the pathogenesis of infection and of the variety of antibody and cellular responses that are induced by the virus. The knowledge created by the studies in nonhuman primates, although important, has not necessarily been proven applicable in humans and thus an effective vaccine has been elusive. The combined lack of a fully predictive animal model ('mice lie and monkeys exaggerate') and lack of defined markers of immune protection against HIV-1 necessitate that HIV vaccines be tested directly for efficacy in phase IIb/III efficacy trials in human volunteers at risk. A trial conducted in Thailand showed moderate but significant protection against infection. SUMMARY: The process of HIV vaccine development is slow, costly and tedious. However, recent preclinical and clinical results have fortunately been a source of renewed optimism in the field.

Report of the 7th meeting on Evaluation of Pandemic Influenza Vaccines in Clinical Trials, World Health Organization, Geneva, 17-18 February 2011.

On February 17-18, 2011, the World Health Organization convened the 7th meeting on "The Evaluation of Pandemic Influenza Vaccines in Clinical Trials" to review the progress made on pandemic A (H1N1) 2009 vaccines and the evaluation of their effectiveness in the field, especially in children less than 3 years of age and in pregnant women. Other topics to be addressed included a comparison of egg- and cell culture-based influenza vaccines, technical issues related to vaccine strain development and vaccine potency, and the status of development of prototype influenza vaccines using new technologies. Pandemic A (H1N1) vaccines were safe in young children, pregnant women and immunocompromized individuals. Overall effectiveness of inactivated A (H1N1) vaccines for all ages was found to vary between 72% and 100% in different countries and with different vaccine preparations. Effectiveness of pandemic A (H1N1) 2009 live attenuated vaccine was estimated to be approximately 80% in pediatric populations in the USA. A single dose of inactivated vaccine adjuvanted with AS03, MF59 or AF03 induced protective immunity in young children and pregnant women. However, unadjuvanted vaccines as well as low dose adjuvanted vaccines (1.9 µg HA) required two doses to elicit protective antibody levels in these populations. Clinical trials of influenza vaccines developed using new technologies showed they were well tolerated and induced antibody and/or T cell immune responses to viral proteins. Further studies are warranted to validate novel immunological criteria for evaluation and licensing of such new influenza vaccine concepts. On the regulatory side, work should be undertaken to harmonize the results of serological tests used to evaluate the immunogenicity of traditional influenza vaccines.

Human immunodeficiency virus (HIV) immunopathogenesis and vaccine development: a review.

The development of a safe, effective and globally affordable HIV vaccine offers the best hope for the future control of the HIV-1 pandemic. Since 1987, scores of candidate HIV-1 vaccines have been developed which elicited varying degrees of protective responses in nonhuman primate models, including DNA vaccines, subunit vaccines, live vectored recombinant vaccines and various prime-boost combinations. Four of these candidate vaccines have been tested for efficacy in human volunteers, but, to the exception of the recent RV144 Phase III trial in Thailand, which elicited a modest but statistically significant level of protection against infection, none has shown efficacy in preventing HIV-1 infection or in controlling virus replication and delaying progression of disease in humans. Protection against infection was observed in the RV144 trial, but intensive research is needed to try to understand the protective immune mechanisms at stake. Building-up on the results of the RV144 trial and deciphering what possibly are the immune correlates of protection are the top research priorities of the moment, which will certainly accelerate the development of an highly effective vaccine that could be used in conjunction with other HIV prevention and treatment strategies. This article reviews the state of the art of HIV vaccine development and discusses the formidable scientific challenges met in this endeavor, in the context of a better understanding of the immunopathogenesis of the disease.

Report of the 6th meeting on the evaluation of pandemic influenza vaccines in clinical trials World Health Organization, Geneva, Switzerland, 17-18 February 2010.

On February 17-18, 2010, the World Health Organization (WHO) convened the 6th meeting on the "Evaluation of pandemic influenza vaccines in clinical trials" to review the progress made on new A (H1N1) 2009 vaccines and prototype H5N1 vaccines and their evaluation in clinical trials. A number of vaccine types were reviewed, including classical egg-derived and cell culture-derived inactivated vaccines, such as split virus or whole-virion vaccines, and live-attenuated vaccines (LAIV), as well as vaccines developed using new technologies. The amount of antigen needed, the effect of adjuvants and the number of doses required to induce adequate antibody responses in various populations, together with the issue of safety of the vaccines, were major topics of the meeting. The effectiveness of H1N1 vaccines and the need for standardization of vaccine potency tests were also discussed. Independent of the vaccine type and the presence or absence of an adjuvant, all A (H1N1) 2009 vaccines were well tolerated, eliciting only mild to moderate local or systemic reactions. For most vaccines tested, a single dose was sufficient to elicit a potentially protective antibody response in the majority of vaccinees >10 years of age. However, a second dose of vaccine was needed to boost immune responses in infants and toddlers 6 months to 3 years of age and, with some vaccines, in children aged 3-9 years.

The 2009 A (H1N1) influenza virus pandemic: A review.

In March and early April 2009 a new swine-origin influenza virus (S-OIV), A (H1N1), emerged in Mexico and the USA. The virus quickly spread worldwide through human-to-human transmission. In view of the number of countries and communities which were reporting human cases, the World Health Organization raised the influenza pandemic alert to the highest level (level 6) on June 11, 2009. The propensity of the virus to primarily affect children, young adults and pregnant women, especially those with an underlying lung or cardiac disease condition, and the substantial increase in rate of hospitalizations, prompted the efforts of the pharmaceutical industry, including new manufacturers from China, Thailand, India and South America, to develop pandemic H1N1 influenza vaccines. All currently registered vaccines were tested for safety and immunogenicity in clinical trials on human volunteers. All were found to be safe and to elicit potentially protective antibody responses after the administration of a single dose of vaccine, including split inactivated vaccines with or without adjuvant, whole-virion vaccines and live-attenuated vaccines. The need for an increased surveillance of influenza virus circulation in swine is outlined.

HIV/AIDS vaccines: a need for new concepts?

HIV vaccine research is at a crossroads carefully contemplating on the next path. The unexpected results of the Merck vaccine trial, while providing a stunning blow to a field in dire need of a protective vaccine, has also raised several fundamental questions regarding the candidate immunogen itself, preexisting immunity to vaccine vectors, surrogate assays and animal models used for assessing preclinical protective responses, as well as relevant endpoints to be measured in a clinical trial. As a result, the research community is faced with the daunting task of identifying novel vaccine concepts and products to continue the search. This review highlights and addresses some of the scientific and practical concerns.

Mucosal immunity and HIV/AIDS vaccines. Report of an International Workshop, 28-30 October 2007.

In October 2007, a joint ANRS-NIH workshop was held on "Mucosal immunity and HIV/AIDS vaccines" in Veyrier-du-Lac, France. Goal of the meeting was to discuss recent developments in the understanding of viral entry and dissemination at mucosal surfaces, rationale for designing vaccines to elicit mucosal immune responses by various routes of immunization, and the types of immune responses elicited. Lessons were drawn from existing vaccines against viral mucosal infections, from the recent failure of the Merck Ad5/HIV vaccine and from attempts at mucosal immunization against SIV. This report summarizes the main concepts and conclusions that came out of the meeting.

The global eradication of poliomyelitis: progress and problems.

Encouraged by the success of the global smallpox eradication certified in 1980, the global poliomyelitis eradication program was launched in 1988 by the World Health Organization (WHO). In addition to routine polio immunization included in the Expanded Program of Immunization (EPI), two major activities were planned: mass polio vaccination campaigns and surveillance of all cases of acute flaccid paralysis. In 2000, the disease had been eliminated from most countries in the world. However, as of 2002, the community acceptance of vaccination was endangered in some countries by rumors about assumed adverse effects of oral polio vaccine. The rejection of polio immunization provided a worrying resurgence of polio in Northern Nigeria, followed by re-infection of 21 countries, whereas resurgence of the disease also was observed in Northern India. Supplementary vaccination activities were resumed, additional resources were mobilized and, in 2007, most re-infected countries became polio-free again. Today, polio remains endemic in only four countries. The goal of global polio eradication has now been set at 2010, but doubts have been expressed about the feasibility of its achievement.

A review of human vaccine research and development: malaria.

The last several years have seen significant progress in the development of vaccines against malaria. Most recently, proof-of-concept of vaccine-induced protection from malaria infection and disease was demonstrated in African children. Pursued by various groups and on many fronts, several other candidate vaccines are in early clinical trials. Yet, despite the optimism and promise, an effective malaria vaccine is not yet available, in part because of the lack of understanding of the types of immune responses needed for protection, added to the difficulty of identifying, selecting and producing the appropriate protective antigens from a parasite with a genome of well over five thousand genes and to the frequent need to enhance the immunogenicity of purified antigens through the use of novel adjuvants or delivery systems. Insufficient clinical trial capacity and normative research functions such as local ethical committee reviews also contribute to slow down the development process. This article attempts to summarize the state of the art of malaria vaccine development.