Controlled Human Infection Models To Accelerate Vaccine Development.

The timelines for developing vaccines against infectious diseases are lengthy, and often vaccines that reach the stage of large phase 3 field trials fail to provide the desired level of protective efficacy. The application of controlled human challenge models of infection and disease at the appropriate stages of development could accelerate development of candidate vaccines and, in fact, has done so successfully in some limited cases. Human challenge models could potentially be used to gather critical information on pathogenesis, inform strain selection for vaccines, explore cross-protective immunity, identify immune correlates of protection and mechanisms of protection induced by infection or evoked by candidate vaccines, guide decisions on appropriate trial endpoints, and evaluate vaccine efficacy.

WHO informal consultation on regulatory considerations for evaluation of the quality, safety and efficacy of RNA-based prophylactic vaccines for infectious diseases, 20-22 April 2021.

This paper presents the key outcomes of the above WHO informal consultation with global stakeholders including regulatory authorities, vaccine developers and manufacturers, academia and other international health organizations and institutions involved in the development, evaluation and use of messenger RNA (mRNA) vaccines. The aim of the consultation was to further clarify the main principles to be presented in an upcoming WHO guidance document on the regulatory considerations in evaluating the quality, safety and efficacy of mRNA prophylactic vaccines for infectious diseases. This WHO guidance document is intended to facilitate global mRNA vaccine development and regulatory convergence in the assessment of such vaccines.

WHO informal consultation on the guidelines for evaluation of the quality, safety, and efficacy of DNA vaccines, Geneva, Switzerland, December 2019.

Consultations have been held to promote the revision of the WHO guidelines for assuring the quality and nonclinical safety evaluation of DNA vaccines adopted by the Expert Committee on Biological Standardization (ECBS) in 2005. The drivers for this revision are described, including the need for regulatory convergence highlighted by the WHO R&D Blueprint. These consultations have driven the revision to its current form, where a new guideline that includes quality, nonclinical, and clinical evaluation of plasmid DNA vaccines is being prepared for public consultation with a view to present to an upcoming ECBS.

Unique safety issues associated with virus-vectored vaccines: Potential for and theoretical consequences of recombination with wild type virus strains.

In 2003 and 2013, the World Health Organization convened informal consultations on characterization and quality aspects of vaccines based on live virus vectors. In the resulting reports, one of several issues raised for future study was the potential for recombination of virus-vectored vaccines with wild type pathogenic virus strains. This paper presents an assessment of this issue formulated by the Brighton Collaboration.

Adventitious agents and live viral vectored vaccines: Considerations for archiving samples of biological materials for retrospective analysis.

Vaccines are one of the most effective public health medicinal products with an excellent safety record. As vaccines are produced using biological materials, there is a need to safeguard against potential contamination with adventitious agents. Adventitious agents could be inadvertently introduced into a vaccine through starting materials used for production.

Review of efficacy trials of HIV-1/AIDS vaccines and regulatory lessons learned: A review from a regulatory perspective.

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.

Scientific and regulatory challenges in evaluating clinical trial protocols for HIV-1/AIDS vaccines - A review from a regulatory perspective.

Clinical development of prophylactic HIV/AIDS vaccines presents many scientific challenges that result in challenges for regulators reviewing clinical trial applications (CTAs). The World Health Organization (WHO) has the responsibility to provide technical support to these regulators. The search for an HIV/AIDS vaccine will only succeed through well-designed, -conducted and -controlled human efficacy studies reviewed and approved by regulators in countries worldwide, particularly in countries where the epidemic has hit hardest, such as in sub-Saharan Africa and Asia.

Human challenge trials in vaccine development: Strasbourg, September 29 - October 1, 2014.

An international workshop to discuss the role of Human Challenge Trials (HCT) in vaccine development was held in Strasbourg, France from 29 September to 1 October 2015. In addition to scientific presentations, several panel discussions focused on key questions and proposed recommendations, including the acknowledgement that HCT have proven to be useful tools to explore vaccine targets, identify immune correlates of protection, and evaluate clinical efficacy, and when appropriate they should be continued and encouraged. In some cases, a HCT may be the only feasible way to move forward with development of an investigational product.

First-in-Human Evaluation of the Safety and Immunogenicity of a Recombinant Vesicular Stomatitis Virus Human Immunodeficiency Virus-1 gag Vaccine (HVTN 090).

Background.  We report the first-in-human safety and immunogenicity evaluation of a highly attenuated, replication-competent recombinant vesicular stomatitis virus (rVSV) human immunodeficiency virus (HIV)-1 vaccine. Methods.

WHO consultation on clinical evaluation of vaccines, 17-18 July 2014, WHO Headquarters, Geneva, Switzerland.

A World Health Organization (WHO) consultation on guidelines for National Regulatory Authorities (NRAs) and vaccine manufacturers on clinical evaluation of vaccines was held from 17 to 18 July 2014, to review key scientific challenges that regulators have been facing since the establishment of the WHO Guidelines on Clinical Evaluation of Vaccines. The guidelines, adopted by the WHO Expert Committee on Biological Standardization (ECBS) in 2001, have served as the basis for setting or updating national requirements for the evaluation and licensing of a broad range of vaccines as well as for WHO vaccine prequalification. Regulators from Australia, Brazil, China, Canada, Germany, India, Republic of Korea, South Africa, United States of America and the United Kingdom were represented.

Now that you want to take your HIV/AIDS vaccine/biological product research concept into the clinic: what are the "cGMP"?

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.

The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG).

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.

Adventitious agents in viral vaccines: lessons learned from 4 case studies.

Since the earliest days of biological product manufacture, there have been a number of instances where laboratory studies provided evidence for the presence of adventitious agents in a marketed product. Lessons learned from such events can be used to strengthen regulatory preparedness for the future. We have therefore selected four instances where an adventitious agent, or a signal suggesting the presence of an agent, was found in a viral vaccine, and have developed a case study for each.

Systematic evaluation of in vitro and in vivo adventitious virus assays for the detection of viral contamination of cell banks and biological products.

Viral vaccines and the cell substrates used to manufacture them are subjected to tests for adventitious agents, including viruses, contaminate. Some of the compendial methods (in vivo and in vitro in cell culture) were established in the mid-20th century. These methods have not been subjected to current assay validation, as new methods would need to be.

Opinion on adventitious agents testing for vaccines: why do we worry so much about adventitious agents in vaccines?

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.

Potential use of inflammation and early immunological event biomarkers in assessing vaccine safety.

Highly effective vaccines have traditionally been designed in a rather empirical way, often with incomplete understanding of their mode of action. Full assessment of efficacy and reactogenicity takes time and, as a result, vaccine introduction to the market is usually slow and expensive. In addition, in rare cases, unacceptable reactogenicity may only become apparent after years of development or even widespread use.

Adventitious agents, new technology, and risk assessment, 19-20 May 2011, Baltimore, MD.

In May 2011, the International Alliance for Biological Standardization, with the cooperation of WHO, FDA, and NIAID, organized a conference on adventitious agents that might be found in biological products using new technology (http://www.iabs.org/index.

Evaluation of the human host range of bovine and porcine viruses that may contaminate bovine serum and porcine trypsin used in the manufacture of biological products.

Current U.S. requirements for testing cell substrates used in production of human biological products for contamination with bovine and porcine viruses are U.

Mode of action of adjuvants: implications for vaccine safety and design.

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.

Biodistribution and toxicological safety of adenovirus type 5 and type 35 vectored vaccines against human immunodeficiency virus-1 (HIV-1), Ebola, or Marburg are similar despite differing adenovirus serotype vector, manufacturer's construct, or gene inserts.

The Vaccine Research Center has developed vaccine candidates for different diseases/infectious agents (including HIV-1, Ebola, and Marburg viruses) built on an adenovirus vector platform, based on adenovirus type 5 or 35. To support clinical development of each vaccine candidate, pre-clinical studies were performed in rabbits to determine where in the body they biodistribute and how rapidly they clear, and to screen for potential toxicities (intrinsic and immunotoxicities). The vaccines biodistribute only to spleen, liver (Ad5 only), and/or iliac lymph node (Ad35 only) and otherwise remain in the site of injection muscle and overlying subcutis.

An overview of animal cell substrates for biological products.

The issue of which cells to use as substrates for the production of biological products, and especially vaccines, has been with us in one form or another ever since the development of cell cultures in the 1950s. The major cell substrate events that occurred over the past 50 years are reviewed briefly. Although numerous conferences were held during that period, incomplete resolution of some cell substrate issues has remained.

Inclusion of adolescents in preventive HIV vaccine trials: public health policy and research design at a crossroads.

The search for a safe effective HIV vaccine has been a centerpiece of HIV research for almost 2 decades. More than 60 clinical HIV vaccine trials have been conducted to date. Several promising candidate HIV vaccines are in advanced clinical development.

Mechanism of ad5 vaccine immunity and toxicity: fiber shaft targeting of dendritic cells.

Recombinant adenoviral (rAd) vectors elicit potent cellular and humoral immune responses and show promise as vaccines for HIV-1, Ebola virus, tuberculosis, malaria, and other infections. These vectors are now widely used and have been generally well tolerated in vaccine and gene therapy clinical trials, with many thousands of people exposed. At the same time, dose-limiting adverse responses have been observed, including transient low-grade fevers and a prior human gene therapy fatality, after systemic high-dose recombinant adenovirus serotype 5 (rAd5) vector administration in a human gene therapy trial.

Phase 1 safety and immunogenicity evaluation of a multiclade HIV-1 candidate vaccine delivered by a replication-defective recombinant adenovirus vector.

Background: The development of an effective human immunodeficiency virus (HIV) vaccine is a high global priority. Here, we report the safety, tolerability, and immunogenicity of a replication-defective recombinant adenovirus serotype 5 (rAd5) vector HIV-1 candidate vaccine.

Methods: The vaccine is a mixture of 4 rAd5 vectors that express HIV-1 subtype B Gag-Pol fusion protein and envelope (Env) from subtypes A, B, and C.