Vaccine Development Process Research Articles

Executive summary and recommendations from the WHO/UNAIDS/IAVI expert group consultation on ‘Phase IIB-TOC trials as a novel strategy for evaluation of preventive HIV vaccines’, 31 January–2 February 2006, IAVI, New York, USA

This report summarizes the discussions and recommendations from a consultation held in New York City, USA (31 January-2 February 2006) organized by the joint World Health Organization-United Nations Programme on HIV/AIDS HIV Vaccine Initiative and the International AIDS Vaccine Initiative. The consultation discussed issues related to the design and implementation of phase IIB 'test of concept' trials (phase IIB-TOC), also referred to as 'proof of concept' trials, in evaluating candidate HIV vaccines and their implications for future approval and licensure. The results of a single phase IIB-TOC trial would not be expected to provide sufficient evidence of safety or efficacy required for licensure. In many instances, phase IIB-TOC trials may be undertaken relatively early in development, before manufacturing processes and capacity are developed sufficiently to distribute the vaccine on a large scale. However, experts at this meeting considered the pressure that could arise, particularly in regions hardest hit by AIDS, if a phase IIB-TOC trial showed high levels of efficacy. The group largely agreed that full-scale phase III trials would still be necessary to demonstrate that the vaccine candidate was safe and effective, but emphasized that governments and organizations conducting trials should consider these issues in advance. The recommendations from this meeting should be helpful for all organizations involved in HIV vaccine trials, in particular for the national regulatory authorities in assessing the utility of phase IIB-TOC trials in the overall HIV vaccine research and development process.

Lower Urinary Tract Symptoms and Erectile Dysfunction: Emerging Concepts

The authorization of several high-efficacy vaccines for use against the novel SARS-CoV2 virus signals a transition in the global COVID-19 response. Vaccine acceptance is critical for pandemic control and has a variety of context- specific drivers that operate at the individual, group, and sociopolitical levels. Social and behavior change interventions can influence individual knowledge, attitudes, and intentions as well as community norms to facilitate widespread vaccine uptake. While considerable research has been done to explore vaccine confidence in high-income populations as well as with respect to childhood vaccinations, much work remains to be done in understanding attitudes and intentions in low and middle income countries for adult or novel vaccines. We conducted in-depth interviews with individuals who had recovered from COVID-19 (n = 8), people who had lost a family member to COVID-19 (n = 4), and health providers (n = 17). We also conducted focus group discussions with members of the general population (n = 24 groups) to explore social norms and community perceptions related to COVID-19, including prevention behaviors, stigma, and vaccines. Researchers collected data in Abidjan, Côte d’Ivoire, in November 2020. In considering whether to accept a future COVID-19 vaccine or not, individuals in the study weighed perceived risk of the vaccine against the severity of the disease. Perceived severity of rumored side effects or safety issues of vaccines were also a factor. Convenience was a secondary, albeit also important, consideration. While concerns about vaccine safety tended to produce an expressed intention to delay vaccination, conspiracy theories about those developing and promoting vaccines and their motives led people to say they would opt out entirely. Behavior change interventions must raise awareness and address misunderstandings about the purpose of vaccines, transparently communicate about vaccine safety and development processes, and engage trusted influencers to build an enabling environment for COVID-19 vaccine roll out.

Design of Vaccine Equivalence/Non-Inferiority Trials with Correlated Multiple Binomial Endpoints

Immunogenicity trials that study the immune responses to vaccination are often used in the vaccine development process as alternatives to clinical efficacy trials. The comparisons of immune responses among various treatment groups are conducted in a non-inferiority or equivalence framework. When there exists a level of immune response that correlates with protection against disease, it is of interest to compare the proportion of responders as defined as response above a specific level or as a predefined increase in immune levels for post-vaccination levels above pre-vaccination levels. Since vaccines often contain several antigens, the correlations between the immune responses need to be taken into account in the analysis. In this paper, we describe appropriate testing methods for demonstrating the non-inferiority/equivalence of two treatments on each of the binomial endpoints. We conduct a comprehensive simulation study to shed light on how the Type I error and power are affected and to what extent when correlated multiple binomial endpoints are present in the vaccine trials. We also illustrate the computation of power for assessment of non-inferiority/equivalence in real studies.

Progress towards the development of malaria vaccines

The misery and suffering caused worldwide by infection with the malaria parasite, especially Plasmodium falciparum, has been well documented. Although no licensed vaccine against malaria currently exists, progress has accelerated in recent years towards the goal of developing one. Although the complexity of the malaria parasite has made the malaria vaccine development process tenuous, advances in science and in the vaccine development process as well as increases in funding are encouraging. These advances, coupled with the results of the recent clinical trial of the vaccine candidate RTS,S, have added new vigor to the idea that a malaria vaccine is not only possible but probable.

Granulocyte contamination dramatically inhibits spot formation in AIDS virus-specific ELISpot assays: Analysis and strategies to ameliorate

The interferon-γ (IFNγ) ELISpot assay has become the most critical tool for HIV vaccine evaluation. External factors affecting ELISpot results must be minimized for the data to be reliably used in vaccine research and development processes. In pre-clinical pigtail macaque studies analyzing HIV/SIV vaccine studies, we detected a strong correlation between levels of granulocytes contaminating PBMC preparations and reduction in the quality and quantity of spots in the IFNγ ELISpot assay. Acute SHIV infection of macaques worsened granulocyte contamination of PBMC fractions and made the assay much less reliable in detecting SIV-specific T cell immunity compared to intracellular cytokine staining (ICS). This problem could be ameliorated by using an F(ab) 2 form of the MD-1 IFNγ capture antibody, presumably reflecting that activation of granulocytes in the well by the Fc portion of the standard capture antibody disrupts spot formation. Improving the standard ELISpot assay by using an F(ab) 2 capture antibody should make it more reliable for use in critical vaccine development studies.

SARS, possible zoonosis in the area of conflict of pathogenic coronaviruses of animals

Severe acute respiratory syndrome (SARS) is an emerging disease, which was first recognized in Guangdong Province, China, in November 2002. In the meantime, SARS has been recognized in patients on all five continents. A novel coronavirus, which is not related to the hitherto known coronaviruses, has been proven to be associated with the disease. Our genomic analyses strongly suggest that the new SARS-coronavirus did not emerge through mutation or recombination and that it has probably been transmitted from a so far not identified animal species to humans. Therefore, it is most likely that SARS virus is a zoonotic agent. A broad body of knowledge originating from research in veterinary medicine indicates that development of vaccines against the SARS-coronavirus may be problematic. The potential danger of such vaccines should not be neglected during the process of vaccine development.

Candidate HIV/AIDS vaccines

Candidate HIV/AIDS vaccines

Research Translation in South Africa

It is estimated that 5 million South African adults and children are currently living with HIV/AIDS and because the scientific consensus is that an AIDS vaccine is the only way of curbing this pandemic, the South African HIV Vaccine Action Campaign (SA HIVAC) was established in 2000 as a community mobilisation and preparedness campaign to inform and educate the South African population about the HIV/AIDS vaccine development process. SA HIVAC includes an Information Clearinghouse whose role is to create an information system providing for the collection, storage and retrieval of information with the necessary architecture. This article describes the Information Clearinghouse's activities.

Addressing vulnerabilities in developing countries.

The UNAIDS guidance document Ethical Considerations in HIV Preventive Vaccine Research as its title implies contextualizes the ethical concerns in the arena of vaccine development in HIV. It seems that UNAIDS decided to develop a rather comprehensive list of guidance points independent of the revisions to the Helsinki declaration. Confronted with a particular problem of the developing world i.e. the rapid spread of HIV and the related issue of the need to carry out candidate vaccine trials in developing countries this UNAIDS publication is very timely. Ethical guidelines in the UNAIDS document are thus expected to speed up the process of vaccine development by providing more specific guidance that could eventually assist the developing countries to contain the spread of AIDS following successful deployment of vaccination programs by sharing the burdens and benefits of such trials. This paper attempts to answer two questions: Do we need to do more about the vulnerabilities of research subjects in the developing world? Are these guidelines enough to enhance the ethical practice in vaccine trials? (excerpt)

Respiratory Syncytial Virus Genetic and Antigenic Diversity

Respiratory syncytial virus (RSV) is a major cause of viral lower respiratory tract infections among infants and young children in both developing and developed countries. There are two major antigenic groups of RSV, A and B, and additional antigenic variability occurs within the groups. The most extensive antigenic and genetic diversity is found in the attachment glycoprotein, G. During individual epidemic periods, viruses of both antigenic groups may cocirculate or viruses of one group may predominate. When there are consecutive annual epidemics in which the same group predominates, the dominant viruses are genetically different from year to year. The antigenic differences that occur among these viruses may contribute to the ability of RSV to establish reinfections throughout life. The differences between the two groups have led to vaccine development strategies that should provide protection against both antigenic groups. The ability to discern intergroup and intragroup differences has increased the power of epidemiologic investigations of RSV. Future studies should expand our understanding of the molecular evolution of RSV and continue to contribute to the process of vaccine development.

Respiratory syncytial virus genetic and antigenic diversity.

Respiratory syncytial virus (RSV) is a major cause of viral lower respiratory tract infections among infants and young children in both developing and developed countries. There are two major antigenic groups of RSV, A and B, and additional antigenic variability occurs within the groups. The most extensive antigenic and genetic diversity is found in the attachment glycoprotein, G. During individual epidemic periods, viruses of both antigenic groups may cocirculate or viruses of one group may predominate. When there are consecutive annual epidemics in which the same group predominates, the dominant viruses are genetically different from year to year. The antigenic differences that occur among these viruses may contribute to the ability of RSV to establish reinfections throughout life. The differences between the two groups have led to vaccine development strategies that should provide protection against both antigenic groups. The ability to discern intergroup and intragroup differences has increased the power of epidemiologic investigations of RSV. Future studies should expand our understanding of the molecular evolution of RSV and continue to contribute to the process of vaccine development.

Vaccines and diagnostic tools for animal health: the influence of biotechnology

Development of improved vaccine and diagnostic-based disease control strategies has benefited considerably from advances in biotechnology, particularly those relating to recombinant DNA technology. Efficiency of the vaccine development process has been increased at all levels, from the analysis of immune responses to the production and delivery of protective antigens to the target species. Serological analysis of antibody prevalence has also become more straightforward as a result of the availability of recombinant pathogen proteins. However, greatest advances arising from biotechnological development relate to the detection and characterisation of pathogens in infected hosts. Probably the most significant development in this regard, which impacts both vaccine and diagnostic development, is the polymerase chain reaction. With the advent of DNA-based antigen delivery vehicles, it is conceivable that protein-based vaccine and diagnostic systems will have been superseded by DNA-based systems by the middle of the 21st century.

Can HIV infection be prevented with a vaccine?

The global human immunodeficiency virus type 1 (HIV-1) epidemic is devastating many communities and a well tolerated and effective vaccine is urgently required. Several lines of evident suggest that vaccine-induced protective immunity can be achieved. This evidence includes individuals shown to have natural immunity, and the partially effective immune responses that are generated during natural infection. However, the obstacles to HIV-1 vaccine development are enormous. The only substantially effective vaccine studied in pathogenic animal models (live, attenuated vaccines) is at present far too unsafe. The only HIV-1 vaccine to proceed to efficacy trials (an envelope protein approach) has been disappointing in its immunogenicity and efficacy in preliminary trials. The antigenic variability of HIV-1 strains is also a great obstacle. Unfortunately, commercial realities also do not favour the expensive development of HIV-1 vaccines required most urgently in less developed countries. Despite these obstacles, there is cause for cautious optimism. Better tolerated HIV-1 vaccine approaches are currently showing great promise in primate models and preliminary clinical trials. Many governments and the World Bank are now providing the political will and funding necessary to fast-track HIV-1 vaccine development. Given sufficient long term scientific and commercial commitment to the HIV-1 vaccine development process, it is ultimately likely that a preventative HIV-1 vaccine will emerge.

A murine model of intranasal immunization to assess the immunogenicity of attenuated Salmonella typhi live vector vaccines in stimulating serum antibody responses to expressed foreign antigens

The lack of a practical small animal model to study the immunogenicity of Salmonella typhi-based live vector vaccines expressing foreign antigens has seriously impeded the vaccine development process. For some foreign antigens, stimulation of serum IgG antibody is the desired, protective immune response. We administered to mice, by orogastric or intranasal (i.n.) routes, attenuated ΔaroC ΔaroD S. typhi CVD 908 carrying a plasmid encoding fragment C (fragC) of tetanus toxin fused to the eukaryotic cell receptor binding domain of diphtheria toxin (fragC-bDt), and monitored serum antibody. While orogastric inoculation of three doses was not immunogenic, i.n. immunization elicited high titers of serum IgG tetanus antitoxin, generating peak ELISA geometric mean titers (GMT) of 27024 and 35658 with 10 8 and 10 9 c.f.u. dosages, respectively; 10 9 c.f.u. i.n. of an ΔaroA S. typhimurium live vector stimulated a peak antitoxin GMT of 376 405. Mice immunized with the S. typhi live vector were 100% protected against challenge with 100 50% lethal doses of tetanus toxin that rapidly killed all control mice. Intranasal immunization with two doses of S. typhi expressing unfused fragment C under control of an anaerobically-activated promoter derived from nirB stimulated significantly higher titers of serum neutralizing antitoxin than fused fragC-bDt controlled by the same promoter (GMT 0.10 AU ml −1 vs 0.01 AU ml −1, P=0.0095). Two i.n. doses of S. typhi encoding fragC under control of powerful constitutive promoter lpp led to significantly higher peak serum neutralizing antitoxin titers than the otherwise identical construct utilizing the nirB promoter (peak GMT 0.72 AU ml −1 vs 0.10 AU ml −1, P=0.022). The i.n. route of inoculation of mice may constitute a practical breakthrough that could expedite the development of some S. typhi-based live vector vaccines by allowing, for the first time, quantitative measurement of serum antibody responses to candidate constructs following i.n. mucosal immunization.

The Search for an AIDS Vaccine: Ethical Issues in the Development and Testing of a Preventive HIV Vaccine

ABSTRACT Increasingly, medical and public attention has focused on the potential efficacy of vaccines to prevent HIV infection. This is no surprise: there have been approximately 17 million HIV infections in the world to date, existing treatments for HIV infection have only limited efficacy, and the great majority of the HIV-infected population has essentially no access to even these medications. While biomedical advances in vaccine development are frequently trumpeted in the media, often out of proportion to the substance of the actual accomplishments, debates over the no less contentious ethical and social aspects of HIV-vaccine trials usually remain hidden from public view. It is this imbalance that Dr Christine Grady, successfully, seeks to right.The Search for an AIDS Vaccine is an ambitious work. The first two chapters are devoted to reviewing the history of vaccines, explaining the vaccine development and regulatory processes, and summarizing the major developments in the burgeoning

Development of a whole killed feline leukemia virus vaccine

Summary A whole killed FeLV vaccine was developed. By use of a chromatography method of purification and concentration, the resulting vaccine has been shown to be significantly lower in bovine serum albumin and total protein contents than were the same ingredients in the starting materials. The virus was inactivated or killed as an essential part of the vaccine development process. Vaccination trials with the vaccine without use of adjuvants indicated appreciable virus-neutralizing serum titer (≥ 1:10) in 107 of 110 vaccinated cats. Of 43 cats vaccinated and subsequently challenge exposed with virulent FeLV, only 2 developed persistent virus antigenemia (longer than 1 month), whereas 14 of 22 nonvaccinated control cats developed persistent viremia. In field tests, 2,770 cats from 6 states were vaccinated and observed. Postvaccinal reactions were not observed.