The S protein binds to its receptor, angiotensin-2 (ACE2) through its receptor-binding domain name (RBD) and is proteolytically-activated by human proteases [39]. Respiratory Viruses Acute respiratory tract infections (ARI) constitute a considerable worldwide disease threat and burden that has been made plainly evident by the number of COVID-19 cases caused by SARS-CoV-2 (CoV-2). Usually, influenza virus (flu) is the most widely recognized cause of ARI associated with respiratory illness and substantial disease burden in adults and elderly individuals [1,2]. Beyond CoV-2 and flu there are other respiratory pathogens such as respiratory syncytial virus (RSV), PF-03654746 Tosylate rhinovirus (RV), human metapneumovirus (HMPV), parainfluenza viruses (PIV), and bocaviruses that contribute to worldwide disease burden [2,3]. For example, RSV is usually associated with considerable disease in older (aged 65 years) adults and young children [4,5]. The greatest hurdle for control of respiratory viruses is usually that there are few licensed vaccines and limited antivirals available. Another challenge and concern is usually that contamination with some RNA viruses does not always provide durable protection against reinfection, as is the case with RSV [6], although disease upon reinfection in young adults is usually often ameliorated PF-03654746 Tosylate and typically restricted to the upper respiratory tract Rabbit polyclonal to RAB18 (URT) [7]. This is notable as the goal of immunization is usually to reduce the severity of disease rather than the induction of sterilizing immunity. It is likely that this induction of long-term protective immunity may require more than one infection and more than one dose of vaccine to augment durable humoral immunity. Viral glycoproteins enable virus entry into the host cell through receptor binding and promote virus egress and the release of progeny. Viral surface glycoproteins are the predominant antigens toward which humoral immune responses are directed. Thus, the principal vaccine strategy is usually to induce blocking and/or neutralizing antibodies to these immunogens. 2. Novel Vaccines The goal of vaccination is usually to prevent or reduce disease and control pathogen transmission. Various vaccine approaches may be needed to safeguard high-risk groups that are at the extremes of age, i.e., very young or old, or have underlying conditions or are immune suppressed in order to provide long-lived acquired immunity. However, as respiratory virus contamination chiefly occurs in the respiratory epithelium, serum antibody does not protect the upper respiratory tract [8], and mucosal antibodies wane [9], control of respiratory virus infection is usually a challenge. Thus, development of efficacious live-attenuated vaccines can be challenging as these vaccines are typically less immunogenic than wild type viruses, and if wild type viruses do not induce durable immunity, it is unrealistic to expect attenuated vaccines to improve the vaccination outcome. This is relevant because attenuation PF-03654746 Tosylate and immunogenicity are linked, and these features narrow the therapeutic window. Based on clinical vaccine trials for viruses like RSV, multiple doses of vaccine seem to be needed to achieve practical immunity. RSV is usually a negative-sense, non-segmented enveloped RNA virus causing substantial morbidity and some mortality in adults and children [10,11]. RSV contributes to an estimated 3 million hospitalizations and 60,000 deaths/year globally [12]. Unfortunately, no safe and approved RSV vaccine exists despite numerous attempts using various vaccine strategies in recent decades. The most infamous vaccine strategy for RSV was the formalin-inactivated RSV vaccine (FI-RSV), which induced enhanced disease in young vaccinees when they were subsequently naturally infected with RSV [13,14]. The FI-RSV vaccine caused unexpected enhanced respiratory disease (ERD) and some mortality. Later it was suggested that this poor vaccine outcome was likely linked to the failure to induce neutralizing antibodies, and the failure to generate efficient IFN and CTL responses [15,16]. The outcome of the FI-RSV vaccine trials raised regulatory and safety concerns ultimately hampering RSV vaccine development. Important facets that affect RSV vaccine development are the absence of PF-03654746 Tosylate an ideal animal model and the lack of established correlates of protection. The RSV vaccine conundrum is usually complicated as no animal model fully replicates RSV disease, and all older adults are seropositive but not necessarily guarded. The.