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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
The goal of a preventive HIV vaccine is to induce cell-mediated immune (CMI) responses and subsequently to reduce the plasma viral load at set point and preserve memory CD4+ lymphocytes. As a result, clinical efforts have mainly focused on CMI-inducing vaccines such as DNA and vectors alone or in prime-boost regimens (Belyakov et al., 2008; Esteban, 2009). In a recent Thai efficacy trial (RV144), the first evidence that HIV-1 vaccine protection against HIV-1 acquisition could be achieved was revealed. The results of RV144 indicated that patients with the lowest risk (yearly incidence of 0.23/100 person years) had an apparent efficacy of 40%, while those with the highest risk (incidence of 0.36/100 person years) had an efficacy of 3.7%. This finding suggested that clinical meaningful difference in vaccine efficacy can be detected by means of the difference in the incidence of risk rate. In addition, the vaccine efficacy appeared to decrease with time (e.g., at 12 months, the vaccine efficacy was about 60% and fell to 29% by 42 months). As a result, at a specific time point, sample size required for achieving a desired vaccine efficacy can be obtained by detecting a clinically meaningful difference in the incidence of risk rate at baseline.
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
The goal of a preventive HIV vaccine is to induce cell-mediated immune (CMI) responses and subsequently to reduce the plasma viral load at set point and preserve memory CD4+ lymphocytes. As a result, clinical efforts have mainly focused on CMI-inducing vaccines such as DNA and vectors alone or in prime-boost regimens (Belyakov et al. 2008; Esteban 2009). In a recent Thai efficacy trial (RV144), the data revealed the first evidence that HIV-1 vaccine protection against HIV-1 acquisition could be achieved. The results of RV144 indicated that patients with the lowest risk (yearly incidence of 0.23/100 person-years) had an apparent efficacy of 40%, whereas those with the highest risk (incidence of 0.36/100 person-years) had an efficacy of 3.7%. This finding suggested that clinical meaningful difference in vaccine efficacy can be detected by means of the difference in the incidence of risk rate. In addition, the vaccine efficacy appeared to decrease with time (e.g., at 12 months, the vaccine efficacy was about 60% and fell to 29% by 42 months). As a result, at a specific time point, the sample size required for achieving a desired vaccine efficacy can be obtained by detecting a clinically meaningful difference in the incidence of the risk rate at baseline.
Recent Advances In HIV/AIDS
Published in Anne George, K. S. Joshy, Mathew Sebastian, Oluwatobi Samuel Oluwafemi, Sabu Thomas, Holistic Approaches to Infectious Diseases, 2017
Improving on the efficacy and durability of the RV144 vaccine regimen is a primary focus of current HVTN activities. Recognizing both the immense need and challenge of developing an efficacious HIV vaccine, a novel collaboration has been created between pharmaceutical companies and nonprofit organization, known as the Pox Protein Public Private Partnership (P5). The primary aim of the collaboration is to extend and confirm the RV144 findings in other geographical locations, such as South Africa, and to prepare a path to eventual vaccine licensure.
Nano-vaccines for gene delivery against HIV-1 infection
Published in Expert Review of Vaccines, 2023
Shuang Li, Meng-Yue Zhang, Jie Yuan, Yi-Xuan Zhang
The human immunodeficiency virus type 1 (HIV-1) pandemic remains a devastating infectious pathogen [1,2], with UNAIDS reporting that a total of 38.4 million cases worldwide were infected with HIV until 2021 (https://www.unaids.org/en). Pre-exposure prophylaxis and antiretroviral therapy have revolutionized HIV-1 prevention and treatment, transforming HIV-1 from what used to be regarded as a loss of life sentence to a chronic disease [3–5]. However, effective HIV-1 treatment and prevention demand strict dosing regimens and lifelong medication [6]. In addition, viral rebound inevitably occurs in some HIV-1-infected individuals that are developing drug resistance [7]. Therefore, many experts agree that obliteration of the HIV-1 pandemic still requires valid preventive vaccines [8,9]. Nevertheless, developing an efficient HIV-1 vaccine has been demonstrated to be inordinately hard [10]. To date, a licensed vaccine against HIV-1 has yet to be created. The RV144 trial has been the only clinical trial to demonstrate a significant protection in humans [11]. The vaccine regimen based on a canarypox vector-based vaccine prime and two HIV-1 gp120 boosts in the RV144 trial elicited protective non-neutralizing antibodies against the V1/V2 region of the HIV-1 envelope (Env), resulting in 31.2% efficacy for the prophylaxis of HIV-1 [11].
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
Since 1987, hundreds of HIV-1 vaccine candidates were clinically tested. Up to now, few HIV-1 preventive vaccines were evaluated in phase IIb/III trials [238–241]. Most vaccines work through eliciting protective antibody responses. Vaccine candidates including bivalent recombinant gp120, adenovirus 5 vector expressing HIV antigens alone or in DNA prime/Ad5 boost vaccine combination did not induce HIV-specific antibodies, and failed to protect against HIV infection. Because of the difficulties in generating antibodies that can bind and neutralize HIV virions, the HIV vaccinology field shifted toward generating T-cell responses. An effective HIV vaccine is RV144 achieved to phase III clinical trial. This vaccine contains canarypox vector vaccine ALVAC-HIV (vCP1521) prime and AIDSVAX®gp120 B/E protein boost which showed about 30% protection in Thailand [238]. It was reported that some immune responses including IgG secretion against V1V2 region of Env gp120 were protective, while specific Env plasma IgA increased infection risk [242]. Recently, further vaccination trials are underway to find novel approaches for delivering vaccines, new components for eliciting greater protection, and new adjuvants for inducing effective and durable responses [243,244,245].
Prophylactic HIV vaccine: vaccine regimens in clinical trials and potential challenges
Published in Expert Review of Vaccines, 2020
Punnee Pitisuttithum, Mary Anne Marovich
Development of a safe and effective HIV vaccine preventing HIV infection has been challenging. Two early Phase 3 trials tested a simple regimen using a recombinant bivalent glycoprotein 120 (gp120) vaccine (AIDSVAX B/B, AIDSVAX B/E candidates). The Vax 004 study used AIDSVAX B/B alone and the Vax003 study used AIDSVAX B/E alone and both protein variants failed to show efficacy in preventing HIV-1 infection [4,5]. Two related efficacy trials followed: the STEP study (USA) and the Phambili study (South Africa) used weakened adenovirus (Ad5) vectors (MRKAd5/HIV-1 Gag/Pol/Nef vaccine) which also did not reduce HIV-1 infections [6,7]. However, the ALVAC-HIV (vCP1521) viral vector prime and boosted with AIDSVAX B/E gp120 protein (RV144 study, Thailand) showed a statistically significant reduction in HIV-1 infection. The Kaplan–Meier curve of HIV acquisition in the RV144 study, published in the NEJM (2009), showed an early and clear separation of treatment arms [8]. RV144 study was important because it was the first time any HIV vaccine showed protection and offered the promise that a vaccine is within reach. Correlates of reduced risk (CoR) in the RV144 study were identified and included non-neutralizing antibodies directed to the V1-V2 region of envelope along with other anti-viral antibody-mediated protection. In order to substantiate and improve upon RV144, the Pox Protein Public Private Partnership (P5) was established to redesign and manufacture a similar prime boost vaccine regimen to address the Clade C epidemic. After safety and immunogenicity testing of ALVAC (Clade C) viral vector primed and boost with AIDSVAX Clade C adjuvanted with MF59 met pre-specified go-no go criteria, another efficacy study (HVTN702) with this regimen was launched in 2016. Other vaccine candidates, focusing on improving cellular-based immune responses, using a DNA vaccine prime-rAd5 vaccine boost, did not show efficacy [9].