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The clinical development of prophylactic HIV-1/AIDS vaccines is confounded by numerous scientific challenges and these in turn result in challenges to regulators reviewing clinical trial applications (CTAs). The search for an HIV-1/AIDS vaccine will only succeed through the conduct of well-designed, well-conducted and well-controlled human efficacy studies. This review summarizes relevant context in which HIV vaccines are being investigated and the six completed efficacy trials of various candidate vaccines and regimens, as well as the lessons learned from them relevant to regulatory evaluation. A companion review focuses on the scientific challenges regulators face and summarizes some current candidates in development. The lessons learned from the completed efficacy trials will enable the development of better designed, potentially more efficient efficacy trials in future. This summary, supported by the World Health Organization (WHO), is unique in that it is meant to aid regulators in understanding the valuable lessons gained from experience in the field to date.

The Division of AIDS Vaccine Research Program funds the discovery and development of HIV/AIDS vaccine candidates. Basic researchers, having discovered a potential vaccine in the laboratory, next want to take that candidate into the clinic to test the concept in humans, to see if it translates. Many of them have heard of "cGMP" and know that they are supposed to make a "GMP product" to take into the clinic, but often they are not very familiar with what "cGMP" means and why these good practices are so important. As members of the Vaccine Translational Research Branch, we frequently get asked "can't we use the material we made in the lab in the clinic?" or "aren't Phase 1 studies exempt from cGMP?" Over the years, we have had many experiences where researchers or their selected contract manufacturing organizations have not applied an appropriate degree of compliance with cGMP suitable for the clinical phase of development. We share some of these experiences and the lessons learned, along with explaining the importance of cGMP, just what cGMP means, and what they can assure, in an effort to de-mystify this subject and facilitate the rapid and safe translational development of HIV vaccines.

Recombinant viral vectors provide an effective means for heterologous antigen expression in vivo and thus represent promising platforms for developing novel vaccines against human pathogens from Ebola to tuberculosis. An increasing number of candidate viral vector vaccines are entering human clinical trials. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to improve our ability to anticipate potential safety issues and meaningfully assess or interpret safety data, thereby facilitating greater public acceptance when licensed.

The manner in which viral vaccines are produced in a biological system makes them vulnerable to microbial contamination. Considerable effort is expended to avoid such contamination and to detect it if it occurred. Is this effort warranted, efficient, scientifically sound, and rational? When asked for my opinion on these matters, I agreed to discuss the basis and historical context for why we do what we do and proffer opinion on what we might do instead or in addition, as we look forward to the inclusion of new strategies and methods in our arsenal. Being an advocate of the 3 R's policy, I invite a re-examination of the traditional in vivo methods in particular. I also advocate for a risk-based approach consistent with "Quality by Design" as a more scientific and rational means of addressing these issues. In the end, vaccinologists need to reassure the public that the vaccines they or their children receive are safe and pure and that all reasonable measures are taken to safeguard them.

Evaluating cell substrates for producing vaccines and other biologicals is one of the critical aspects in assuring quality and safety of these products. As part of its mission in setting standards for biological products, WHO provides recommendations for manufacturing and evaluating biologicals. Regular updates of the guidance documents are important to manufacturers and regulators worldwide. WHO Expert Committee on Biological Standardization (ECBS) identified a need for revising the requirements for cell substrates (WHO TRS 878, annex 1). In response, WHO established a Study Group (SG) in 2006 that prepared an updated set of recommendations for using cell substrates for the production of biologicals. A summary of the proposed changes that the SG made in 2007 is available at WHO web site (http://www.who.int/biologicals/publications/meetings/areas/vaccines/cells/en/index.html). Draft revised recommendations were circulated to regulators, manufacturers and other experts for comments in April 2009. The SG held its third meeting on 22-23 April 2009 to review progress in the revision and to propose further improvements. In addition, the experts discussed the need for reference preparations, reference cell banks, and standardization of testing methodologies. The SG proposed clarifications of the rationale for in vivo testing as well as the potential for applying new methods for in vitro testing for detecting microbial agents. In line with this, WHO should conduct review of the current manufacturers' practice in using tests for microbial agents and interpreting these results. Additionally, WHO should take a lead in developing an International Standard for nucleic acid amplification test (NAT) for detecting mycoplasma contamination in cell substrates. WHO Collaborating Centers will lead this initiative, involving other relevant institutions in this area. Finally, advice on the replacement of the WHO Vero reference cell bank 10-87 with respect to the source of cells and re-characterization of the bank was provided. The intended use of the replacement cell bank would be the same as for the current cell bank, which is to serve as a source of well-characterized cells for establishing master cell banks for the production of biologicals. The SG will report outcomes of its discussion to the ECBS at its next meeting in October 2009 for further considerations and advice regarding the proposed course of action.

In summary, this chapter reviews the principles of how the current and routine tests detect adventitious agents, and reviews how novel and emerging methods differ in their detection principles. These facets may permit novel methods to emerge to supplement, refine, or replace the routine methods. We have suggested a framework for risk assessment to assure biosafety in vaccines and suggested quantitative modeling to help crystallize thinking about the place of testing, either routine or novel, in this assurance. We assert that testing for adventitious agents should not be the sole basis on which product biosafety is assured. Appropriate sourcing and quality control of raw and starting materials, adherence to principles of Good Manufacturing Practices, including environmental and personnel monitoring and process validation, and finally, testing as verification are the package needed for maximal assurance of biosafety. Thus, a pathway forward to a new paradigm for adventitious agent testing exists in which detection of a broader array of potential adventitious agents might be included in the testing, with adequate sensitivity to provide the needed assurance of verification that there has been no catastrophic breach, in the context of the overall process, design, and adherence to cGMP. Furthermore, it is our hope that we may be able to implement the 3 Rs policy to reduce, replace, and/or refine the use of animals in product safety testing, at the same time that we provide greater assurance of the biosafety of vaccines.

For decades, the search for new vaccine adjuvants has been largely empirical. A series of new adjuvants and related formulations are now emerging that are acting through identified immunological mechanisms. Understanding adjuvant mechanism of action is crucial for vaccine design, since this allows for directing immune responses towards efficacious disease-specific effector mechanisms and appropriate memory. It is also of great importance to build new paradigms for assessing adjuvant safety at development stages and at regulatory level. This report reflects the conclusions of a group of scientists from academia, regulatory agencies and industry who attended a conference, organized by the International Association for Biologicals (IABS), on the mode of action of adjuvants on 29-30 April 2010 in Bethesda, Maryland, USA, particularly focusing on how understanding adjuvants mode of action can impact on the assessment of vaccine safety and help to develop target-specific vaccines. More information on the conference output can be found on the IABS website, http://www.iabs.org/.

Purpose To report a case of surgically induced necrotizing scleritis (SINS) as a complication of conjunctival autograft after pterygium excision. Methods A 52-year-old man had undergone nasal pterygium excision with conjunctival autograft in the right eye at another facility. He was treated for suspected infective scleritis before presentation. Results The sclera, at the site of prior pterygium excision, showed significant thinning with uveal show. There was active inflammation adjacent to the site of thinning. Systemic studies and the examination were noncontributory. The patient was suspected of having SINS and received pulsed injections of methylprednisolone 1000 mg/d for 3 days. The patient also underwent an emergency scleral patch graft with amniotic membrane graft. Over the next 2 weeks, the scleral graft showed vascularization and was taken well. Conclusions SINS may develop after pterygium surgery with conjunctival autograft. Evidence of connective tissue disease may or may not be found on clinical examination and on laboratory studies. Early diagnosis, prompt immunosuppression, and scleral patch grafting prevents progression and further devastating complications.

The World Health Organization (WHO) has estimated that 40 million individuals are living with HIV-1 as of 2003 (UNAIDS/WHO, 2003). In addition, approximately 14,000 people are newly infected with HIV-1 each day, worldwide (UNAIDS/WHO, 2003). Thus, there is tremendous public health interest in developing safe and effective preventive HIV-1 vaccines. Vaccines have proven to be one of the most effective means of preventing serious infectious diseases. The contribution of vaccines toward markedly decreasing the incidence of many of the once-common childhood infectious diseases has been particularly notable (CDC, 1999). Thus, the public health goal is to develop an effective HIV-1 vaccine that will achieve a similar success in controlling the AIDS epidemic. However, the development of an HIV-1 vaccine has a unique and complex set of scientific, clinical, social, ethical, and economic challenges (Amara and Robinson, 2002; Esparza and Osmanov, 2003; Fast et al., 1995; Goldenthal et al.,1998; Klausner et al., 2003; Nathanson and Mathieson, 2000). Collaborative efforts in the development of an effective HIV-1 vaccine are ongoing among government agencies, academic investigators, and pharmaceutical and biotechnology companies. Even more organization on a global scale has been strongly encouraged (Klausner et al., 2003).

Methods HVTN 090 enrolled sixty healthy, HIV-1-uninfected adults in a randomized, double-blinded, placebo-controlled dose escalation study. Groups of 12 participants received rVSV Indiana HIV Gag vaccine at 5 dose levels (4.6 x 10 to 3.4 x 10 PFU) (N=10/group) or placebo (N=2/group), delivered intramuscularly at 0 and 2 months. Reactogenicity over 7 days, adverse events (AEs), and viral cultures from whole blood, urine, saliva and swabs of oral lesions were collected. HIV-1-specific CD4+ and CD8+ T-cell responses to Gag peptides were measured 1 and 2 weeks post-boost by intracellular cytokine staining.