Page 12 Adam • Evaluation of the Humoral/Fc-mediated Immune Responses… vectors cannot replicate within the host. Therefore, a region of Ad26’s genome that is critical for its replication, the E1 region, is removed - thereby making the Ad26 vectors “replication incompetent.” Interestingly, the location where the E1 region used to be is where the “transgene cassette” (the DNA coding for the HIV-1 antigens) is later placed. Then, since the virus is unable to replicate, when the Ad26 vectors need to be replicated in order to construct the vaccine, “complement cell lines” (such as HEK293 and PER.C6 - which themselves contain the needed E1 region) are used to replicate the Ad26 vectors in. From there, the Ad26 vectors will inevitably be injected into a patient. Once inside the body, the vectors will typically target a number of different cell types, especially epithelial cells. The vectors utilize the Coxsackie and Adenovirus Receptors on the surface of target cells in order to achieve entrance into the target cells. From there, the vector’s DNA genome is released into the cytosol of the target cell and is later shuttled into the cell’s nucleus (though not integrated like HIV-1’s genome.) From there, the target cells begin synthesizing HIV-1 antigens from the Ad26 vector DNA, which are then secreted by the target cells into the extracellular space (Custers et al., 2020; Rauch et al., 2018). Subsequently, DCs can come across the secreted antigens (as well as the gp140 subunits from the accompanying subunit vaccine), endocytose them, process them via the MHC-I and MHC-II pathways, and then begin activating an immune response - B7 expression would have been most-likely already activated via the Ad26 vector itself or by the subunit vaccine’s adjuvant. Thus, with all of this crucial background information in mind, it is important to now look at two key studies, published within the last few years, that detail how well an Ad26 viral vector vaccine, paired with a gp140 subunit vaccine, can elicit the previously mentioned immune correlates of protection against HIV-1 (namely, IgG production, ADCC and/or ADCP), as well as provide insight into how researchers have come to determine the most optimal Ad26 vector/gp140 subunit vaccine regimen. The intention of reviewing the following two critical articles, is to help answer whether or not a combination Ad26 Viral Vector/gp140 subunit prophylactic vaccine regimen elicits sufficient immune correlates of protection against HIV-1 infection to warrant further testing past Phase 1/2a Clinical Trials. Analysis The first study that will be discussed is Barouch et al.’s study, published in 2018, that details the findings of both a human phase 1/2a clinical trial (named APPROACH), as well as contemporary study carried out by the same researchers on rhesus monkeys (called NHP 1319). The explicit goal of these two concurrent studies (combined into one overarching published study), were to help determine which Ad26 viral vector-based vaccine regimens, out of a collection of 7 different combinations, was most optimal for use in future clinical trials. It is important to note that this was the first phase 1/2a clinical trial of a non-prototype Ad26vectored HIV-1 vaccine. Naturally, as a phase 1/2a trial, the researchers were hoping to discover which vaccine combination was the most
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