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Sample Size for Clinical Trials with Extremely Low Incidence Rate
Published in Shein-Chung Chow, Jun Shao, Hansheng Wang, Yuliya Lokhnygina, Sample Size Calculations in Clinical Research: Third Edition, 2017
Shein-Chung Chow, Jun Shao, Hansheng Wang, Yuliya Lokhnygina
A typical example for clinical studies with extremely low incidence rate is clinical trials conducted for preventive HIV vaccine development. In 2008, it was estimated that the total number of people living with HIV was 33.4 million, with 97% living in low- and mid-income countries (UNAIDS, 2009). As a result, the development of a safe and efficacious preventive HIV vaccine had become the top priority in global health for the control of the HIV-1 in the long term. In their excellent review article, Kim et al. (2010) indicated that the immune response elicited by a successful vaccine will likely require both antibodies and T cells that recognize, neutralize, and/or inactivate diverse strains of HIV and that reach the site of infection before the infection becomes irreversibly established (see also Haynes and Shattock, 2008). Basically, the development of HIV vaccine focuses on evaluating vaccines capable of reducing viral replication after infection as the control of viral replication could prevent the transmission of HIV in heterosexual population (Excler, Tomaras, and Russell, 2013), and/or conceivably slow the rate of disease progression as suggested by nonhuman primate (NHP) challenge studies (see, e.g., Mattapallil et al., 2006; Gupta et al., 2007; Watkins et al., 2008).
Sample Size for HIV-1 Vaccine Clinical Trials with Extremely Low Incidence Rate
Published in Cliburn Chan, Michael G. Hudgens, Shein-Chung Chow, Quantitative Methods for HIV/AIDS Research, 2017
Shein-Chung Chow, Yuanyuan Kong, Shih-Ting Chiu
As an example, consider clinical trials for preventive HIV vaccine development. In 2008, it was estimated that the total number of people living with HIV was 33.4 million people, with 97% living in low- and middle-income countries (UNAIDS 2009). As a result, the development of a safe and efficacious preventive HIV vaccine had become the top priority in global health for the control of HIV-1 in the long term. In their excellent review article, Kim et al. (2010) indicated that the immune response elicited by a successful vaccine likely will require both antibodies and T cells that recognize, neutralize, and/or inactivate diverse strains of HIV and that reach the site of infection before the infection becomes irreversibly established (see also Haynes and Shattock 2008). Basically, the development of an HIV vaccine focuses on evaluating vaccines capable of reducing viral replication after infection, as the control of viral replication could prevent transmission of HIV in the heterosexual population (Excler et al. 2013) and/or conceivably slow the rate of disease progression as suggested by nonhuman primate challenge studies (see e.g., Gupta et al. 2007; Mattapallil et al. 2006; Watkins et al. 2008).
Advances and challenges in recombinant Mycobacterium bovis BCG-based HIV vaccine development: lessons learned
Published in Expert Review of Vaccines, 2018
Athina Kilpeläinen, Milena Maya-Hoyos, Narcís Saubí, Carlos Y. Soto, Joan Joseph
Mycobacteria, and especially BCG, are useful bacterial live vaccine vehicles due to their adjuvanticity, safety profile, low cost, suitability for neonates and ability to be mass-produced [11–17,156]. Furthermore, it acts as an adjuvant on its own due to its cell-wall components and lipoproteins [14–17]. In the context of HIV vaccine development, several rBCG-based constructs have been explored and are under development. As extensively reviewed by us and others, rBCG:HIV vaccine candidates have been demonstrated to induce and significantly increase the specific HIV immune responses when coupled with a virally or otherwise vectored boost (Table 1). They have also proven to be able to induce long-lasting HIV-1 specific serum IgG antibodies in guinea pigs [112]. The slow replication and persistence in vivo accompanied by a low antigenic load make vaccination with BCG an attractive choice as a vector for an HIV-1 vaccine, as this has been shown to induce memory T-cell responses in humans and several animal models [157,158]. This type of effector memory T cell response is crucial to battling infection, as was shown by Hansen et al. [159]; where vaccination of Rhesus Macaques with cytomegalovirus vectored SIV vaccines, resulted in protection from SIV challenge, an effect linked to effector memory T cell responses. However, strategies to overcome immunodominance are still necessary to achieve a protective rBCG-based HIV-1 vaccine [120].
Accelerating HIV vaccine development using non-human primate models
Published in Expert Review of Vaccines, 2019
Mohammad Arif Rahman, Marjorie Robert-Guroff
A potent vaccine is indispensable for combatting the HIV pandemic, yet development of such a vaccine has been very difficult in part due to the fact that HIV integrates into the host genome, meaning an effective vaccine will need to completely prevent infection rather than just control disease. Additionally, the spectrum of HIV strains worldwide is extremely diverse due to the high mutability of the virus, and the viral envelope, the main target for eliciting protective immunity, experiences continual changes and escape mutations in response to induced immunity, is poorly immunogenic, and possesses a complex conformational structure complicating vaccine design. Overall, HIV vaccine development is expensive and requires years to navigate the clinical trials process to insure safety, immunogenicity, and ultimately protective efficacy. It is difficult to manipulate HIV vaccination regimens in humans for in-depth evaluation of induced immunity, so animal models are essential. Different vaccine approaches can be tested and immune responses can be monitored at multiple tissue sites followed by challenging the animals with infectious virus to determine protective efficacy. Preclinical animal testing of vaccine candidates can aid vaccine design and development if properly interpreted and can insure only the most promising progress to human trials. Here, we discuss animal models available and their uses and limitations, review the ability of pre-clinical vaccine studies to predict eventual outcome in human clinical trials, and outline how animal studies are facilitating development of new vaccine strategies and movement of promising vaccine candidates into clinical trials.
Antiviral therapy for the sexually transmitted viruses: recent updates on vaccine development
Published in Expert Review of Clinical Pharmacology, 2020
Kimia Kardani, Parya Basimi, Mehrshad Fekri, Azam Bolhassani
Vaccination of STVs is logically important before sexual activity. However, preadolescents are harder to vaccinate than infants and school-entry-age children. The durability of responses and the need for booster doses should be carefully assessed for vaccine reaching licensure. About STVs, some vaccination strategies using specific antigens attracted a special interest. For example, targeting HBZ antigen may be more effective in development of anti-HTLV-1 vaccination. The studies showed that despite the failures in HIV vaccine development, the novel and diverse preclinical and clinical anti-HIV vaccines are underway. Up to now, RV144 is a preventive HIV vaccine used in Thailand. Understanding how immune populations are maintained within mucosal niche to eradicate HIV is important to improve effective preventive/therapeutic approaches. Moreover, an effective vaccine that prevents genital herpes infection is a main concern of public health. An ideal vaccine should prevent both genital lesions and asymptomatic subclinical infection caused by HSV-1 &-2. Three phase III clinical trials using HSV-2 glycoproteins as immunogens were performed over the past 20 years, but none of them were approved to use in human. The success of these vaccine candidates depends on improving animal models to better identify immune correlates of protection. However, the lack of durable immunity and the protection against both types of HSV remained unsolved. Moreover, genital shedding of HSV DNA was a better approach than serology to diagnose subclinical infection in immunized individuals. Indeed, a vaccine that prevents genital lesions without reducing virus shedding may not modify transmission to sex partners.