LAUSR

The World Health Organization (WHO) estimates that influenza annually is the cause of one billion infections, of which 3–5 million are severe diseases, with between 300,000 and 500,000 deaths worldwide. Among pediatric populations, influenza causes more than 800,000 hospitalizations in children of 5 years old and younger and with more than 300,000 hospitalizations in children of ages <1 year old. Vaccination is the primary strategy for the prevention and control of influenza. Indeed, annual influenza vaccination is currently recommended for groups at high risk of complications from influenza infection such as pregnant women, elderly people, young children, people with chronic diseases, and occupational groups [1]. The most widely used vaccines are either killed/inactivated or live attenuated influenza vaccines (LAIVs). The trivalent inactivated vaccines (TIVs) produced annually are currently targeted against the circulating H3N2, the pandemic H1N1/ 09, and an influenza B lineage strain as determined by the WHO. Three formulations are currently available: whole virus, detergent-split, and subunit vaccines, administered intramuscularly or subcutaneously. These vaccines rely on the induction of neutralizing antibodies targeting the globular head of viral hemagglutinin (HA) and neuraminidase (NA) antigens. Recently, quadrivalent inactivated vaccines, including a second influenza B virus in addition to the viruses in trivalent vaccines, have become available and are expected to provide wider protection against influenza B virus infections. The LAIVs, which are administered intranasally, can stimulate humoral response, inducing both secretory IgA (S-IgA) and serum IgG, as well as cell-mediated immune response, similarly to natural influenza infection. However, they do have some limitations; for example, they are currently not approved for use in high-risk groups, due to the high incidence of allergic reactions as well as the risk of transmission following vaccination. Intranasal LAIVs are produced by reverse genetics using the HA and NA genes from circulating viruses on an attenuated, temperature-sensitive, cold-adapted virus backbone. LAIVs were found to be effective in influenza prevention in several controlled trials conducted in children before the A/ H1N12009 pandemic [2]. However, the licensed LAIV in the United States has suffered a number of issues concerning its vaccine effectiveness (VE) over the past three seasons (2013– 2014, 2014–2015, and 2015–2016) [3]. Consequently, in June 2016, the American Advisory Committee on Immunization Practices (ACIP) recommended that LAIV should not be used during the 2016–2017 influenza season, while the same decision was not accepted by several other health authorities such as Canada, UK, and Finland where LAIV VE was considered adequate [4]. Possible explanations for reduced LAIV VE has been a decreased immune response against A/H1N1pdm09 (thought to be the result of a more highly vaccinated population during seasons 2013–2014 and 2015–2016), antigenically drifted A/H3N2 viruses during the 2014–2015 season, potential interference of viruses included in the LAIV, heat susceptibility, and also methodological issues in studies (biases in the design and statistical limits) [5]. Several preclinical studies on adjuvant-combined nasalinactivated vaccines have revealed that nasal S-IgA reacted with homologous virus HA and were cross-reactive with viral HA variants, resulting in protection and cross-protection against infection by both homologous and variant viruses. Data suggest that adjuvant-combined nasal-inactivated vaccines have advantages over the current injectable vaccines because they induce both S-IgA and serum IgG. Moreover, nasal-inactivated vaccines seem to be superior to the LAIV ones because noninfectious preparation could be used also in high-risk populations. Therefore, the development of intranasal-inactivated vaccines has to be recommended [6]. Recently, Protein Sciences have developed a vaccine, Flublok®, based on the HA protein; this is the first recombinant HA vaccine and data from the clinical studies were sufficiently compelling to support its FDA licensure for adults older than 18 years old (initially on 16 January 2013 and expanded on 29 October 2014) for the prevention of influenza (see next sections) [7]. The influenza vaccines available in the USA for 2016–2017 influenza season are summarized in Table 1. The immune response to influenza vaccine is influenced by several host factors, such as age, genetic differences in immune responsiveness, history of infection and previous vaccination against influenza, gender, medical history, and health status.