A Single Dose of a Hybrid hAdV5-Based Anti-COVID-19 Vaccine Induces a Long-Lasting Immune Response and Broad Coverage against VOC  
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September 2021, to 232,075,351 confirmed cases of COVID-19, including 4,752,988 deaths ([[https://covid19.who.int/](https://covid19.who.int/)]([https://covid19.who.int/](https://covid19.who.int/)), accessed on 28 September 2021). During the last months, different regulatory bodies issued emergency use authorization for different vaccines based mainly on mRNA and adenoviral-based platforms [1]. With the sole exception of the hAdV-26-based vaccine. that was approved for one dose administration after showing an efficacy in clinical trials slightly over 65% [2], all the vaccines are given as a prime-boost approach to achieve maximal immune response and protection [3]. Companies are facing challenges in manufacturing vaccines and building the supply chains to meet the demand for COVID-19 vaccines. Different countries prioritized the distribution of a first vaccine dose to as many people as possible [4]. Thus, the need for two doses and the fact that mRNA vaccines require logistically difficult cold-chains [5] make this type of vaccines more challenging to deploy in developing countries, where ultra-low freezers may not be widely available. Therefore, getting a single-dose vaccine with suitable stability and storage properties, that can reach the local population rapidly, is a major challenge for the scientific community, especially in low- and middle-income countries. Despite the unprecedented achievement of having approved vaccines in one year, it is still early to establish the durability and extent of the protection; recent data on the vaccines which first received approval, like BNT162b2, from Pfizer-BioNTech, point to a diminished efficacy already six months after vaccination [6; 7]. Most importantly, the way to optimize the existing vaccines to protect against the prevalent SARS-CoV-2 variants of concern (VOC) that are spreading globally it is still unclear [8]. These VOC have multiple mutations in Spike, mainly in the RBM region and N-terminal domain, that differ substantially from the Spike variants encoded by the already approved vaccines. In fact, all the evidence indicates that serum samples obtained from convalescent people or from vaccines offer diminished protection against the \(\beta\), \(\gamma\) and \(\delta\) variants [9]. Replication-incompetent, adenoviral-based vaccines can induce a long-term adaptive neutralizing humoral and cellular immunity [10]. The prevalence of anti-hAdV5 immunity in the developing world in the past [11] led different academic groups and companies to identify less prevalent human adenovirus serotypes [2; 12] or non-human and primate adenoviral vectors [13] for anti-COVID-19 vaccine development. However, previous studies that compared the immunogenicity induced by hAdV5-based vaccines with the less prevalent human adenovirus hAdV26 and the chimpanzee-derived adenovirus ChAdOx1, among others, demonstrated that hAdV5 induced the most potent immune responses [10; 14; 15]. Moreover, hAdV5 is no longer the most prevalent AdV responsible for pediatric and crowded community outbreaks and was replaced by other hAdVs [16]. In addition, there is preclinical evidence that the annual immunization with the same hAdV vector may be effective due to a significant decline in vector immunity [17]. Real-world evidence also shows that hAdV-specific T cell response declines with age [18]. Moreover, the clinical data obtained with an hAdV5-based COVID-19 vaccine showed that despite the pre-existence of hAdV5-nAbs, 85-100% of volunteers administered with only one shot of an hAdV5-based vaccine showed seroconversion against SARS-CoV-2 [19]. In a two-dose regimen clinical trial with the ChAdOx1-based vaccine, anti-ChAdOx1 nAbs increased with the prime vaccination but not with the boost one; that was in contrast to anti-SARS-CoV-2 nAbs, that continued to increase after the boost at 28 days [20].