100 years since the 1918 influenza pandemic

Introduction

This year marks 100 years since the 1918 influenza pandemic.¹ Historians think that this pandemic started in Kansas in early 1918. By winter 1919, the virus had infected one-third of the global population and killed at least 50 million people (∼5% of the world's population). Three more influenza pandemics have struck since, in 1957, 1968 and 2009, spreading widely but not with as deadly an impact. Many studies on influenza have been performed in recent decades, and thus we have decided to publish a centenary issue in Human Vaccines & Immunotherapeutics. The issue contains 16 Review articles, 14 Research papers, 4 Commentaries and 2 Short Reports on different aspects of influenza virology, vaccines, vaccination strategy, and therapy. Many world-class experts have contributed to present the main findings on the vaccine and this infectious disease, for which a universal vaccine is still elusive.

Virology

Information on circulation of influenza viruses is extremely important for vaccine development. In this centenary issue, Cruz et al. showed that the study of influenza virus evolution in humans has revealed a significant role of glycosylation profile alterations in the viral glycoproteins – hemagglutinin (HA) and neuraminidase (NA), in the emergence of both seasonal and pandemic strains.² Viral antigenic drift can modify the number and location of glycosylation sites, altering a wide range of biological activities and the antigenic properties of the strain. In view of the key role of glycans in determining antigenicity, elucidating the glycosylation profiles of influenza strains is a requirement towards the development of improved vaccines.

Chong et al. highlighted that influenza A/H3N2 viruses are the most common and virulent subtypes for human.³ Antigenic drift, changes in antigenicity through the accumulation of mutations in the HA gene is chiefly responsible for the continuing circulation of A/H3N2 viruses, resulting in frequent updates of vaccine strains based on new variant analyses.

Orsi et al. highlighted that influenza A and B viruses often co-circulate, and influenza B plays an important role in the spread of infection.⁴ A 6-year retrospective surveillance study conducted between 2010 and 2016 showed that the relative proportions of viral lineages varied from year to year and confirmed the need for continuous virological surveillance of seasonal epidemics, bringing attention to the adoption of universal influenza immunization programme in the childhood.

Liu et al. focused on the five epidemic waves of human H7N9 infections between 2013 and 2017.⁵ The fifth wave differed from the previous four waves in that highly pathogenic avian influenza H7N9 viruses with multiple basic amino acids at the cleavage site were detected in humans, poultry and environmental samples.

Overall, experts agree on the importance of a worldwide surveillance of influenza viruses circulation in order to prepare against new viral pandemics.

Vaccines

Influenza prevention through vaccination represents the best way for avoiding influenza-related complications. This centenary issue has dedicated several manuscripts to new research on influenza vaccines.

Smetana et al. showed that the current influenza vaccine formulation remains highly effective in reducing morbidity and mortality when well-matched to circulating strains.⁶ Tregoning et al. summarized data on the use of adjuvants to improve influenza vaccines immunogenicity.⁷ It was shown that adjuvants are particularly beneficial for influenza vaccines administered during a pandemic when a rapid response is required or for use in patients with impaired immune responses, such as infants and the elderly. Hung and Yuen compared intradermal vaccination with various devices with subcutaneous and intramuscular vaccination and discussed the role of topical adjuvant before intradermal vaccination.⁸ Mohn et al. summarized available data on the live attenuated influenza vaccine (LAIV).⁹ They showed that a better understanding of the immune responses after LAIV may aid in achieving the ultimate goal of a future universal influenza vaccine. Stevanovic et al. presented data on their phase I double-blind, randomized, placebo-controlled trial on the safety and immunogenicity of a Serbian-produced seasonal trivalent split, inactivated influenza vaccine in healthy adults.¹⁰

Three articles focused the attention of quadrivalent influenza vaccines. Choi et al. reported data on immunogenicity and safety of VaxigripTetra in 300 Korean adults 18–60 years of age.¹¹ Montalban et al. described the results of an open-label, post-licensure trial to confirm the immunogenicity and safety of the Southern Hemisphere 2015 formulation of the inactivated split-virion quadrivalent influenza vaccine Fluzone Quadrivalent in adults 18–60 years of age and >60 years of age.¹² Sesay et al. reported results from a randomized multicenter phase III trial assessing the lot-to-lot consistency of the 2014–5 Northern Hemisphere quadrivalent split-virion inactivated influenza vaccine, showing that its immunogenicity was superior for the added B strain and safety was similar with that of trivalent inactivated influenza vaccine in younger and older adults.¹³

Moreover, Sarsenvayeva et al. showed that RIBSP 88 and VAXIGRIP have similar immunogenic and safety profiles,¹⁴ whereas Long et al. reported that the wild-type A/Solomon Islands/3/2006 (H1N1) (SI/06wt) could be used for large-scale vaccine production with sufficient safety and efficacy, as confirmed by animal experiments with mice and ferrets.¹⁵

In an effort to ameliorate the fear and pain often associated with routine intramuscular vaccination, Zhou et al. demonstrated the preclinical efficacy of needle-free intradermal delivery of a monovalent H7N9 split vaccine.¹⁶

Among the main problems associated with influenza vaccines, there are those of correlates of protection and safety. Wang et al. followed nursery school children and found that the effectiveness of the trivalent influenza vaccine was compromised in the 2015–6 season by B lineage mismatch.¹⁷ Castrucci et al. described how host factors can contribute to the heterogeneity of immune responses induced by influenza vaccines.¹⁸ Moreover, Ward et al. described attempts to standardize surrogate assays to predict vaccine efficacy, the dangers of over-reliance on reference serologic assays, the ways that manufacturers can exploit the existing regulatory framework to make their products ‘look good’ and the implications of this long-established system for the introduction of novel influenza vaccines.¹⁹ Regarding safety, Trombetta et al. provided an overview of influenza vaccine safety according to target group, vaccine type and production methods, documenting that vaccine safety differs according to the target group, the genetic predisposition of the population, the type of vaccine and production methods.²⁰ Interestingly, Zheng et al. presented data on the first clinical study to evaluate the safety of influenza vaccine in clinically cured leprosy patients as an effort to eradicate discrimination on leprosy.²¹

Vaccination strategies

For an appropriate use of influenza vaccines, it is mandatory to implement appropriate vaccination strategies. Vaccination strategies include different aspects, and the papers included in this centenary issue cover the most important problems.

To inform vaccine updates, laboratories that contribute to the World Health Organization Global Influenza Surveillance and Response System monitor the antigenic phenotypes of circulating viruses all year round. Agor and Ozaltin reviewed the literature on state-of-the-art tools and prediction methodologies utilized in modeling the evolution of influenza to inform vaccine strain selection.²²

Principi et al. highlighted that national influenza immunization policies can vary significantly from country to country.²³ Disparities among countries will be overcome only when more reliable data regarding all these aspects of influenza infection, particularly those related to the true impact of the disease, are precisely defined.

Rizzo et al., applying the methodology of scoping review of grey and scientific literature, described the European and the US approach to influenza vaccine prevention, showing that public health authorities should encourage healthcare workers to vaccinate themselves and to recommend seasonal influenza vaccination to people in the target groups.²⁴

Bonanni et al. showed that health authorities should give general practitioners the opportunity to choose the appropriate vaccines tailored to specific patients,²⁵ whereas Isenor et al. highlighted that people who chose to be vaccinated by community pharmacists reported positive experiences.²⁶

Mahroum et al. demonstrated that health authorities and decision-makers should promote high-quality communication campaigns in order to raise awareness of vaccination practices.²⁷ Moreover, Quinn suggested particular roles and strategies for health care providers, public health agencies, and African American communities and families, which can literally move the needle to increase seasonal influenza vaccination.²⁸

Restivo et al. showed the high effectiveness of influenza vaccination among high-risk groups, representing a tool for public health decision-makers to develop evidence-based preventive interventions to avoid influenza outcomes.²⁹

Other articles focused on hgh-risk groups: the elderly, children, pregnant women and health care workers (HCWs).

Regarding the elderly, Gravenstein et al. documented that high-dose influenza vaccine (HD) with quadruple the dose of antigen in standard-dose vaccine is more efficacious in community-dwelling persons 65 years and older.³⁰ Heo et al. demonstrated that based on cost-effectiveness and budget impact analysis, influenza vaccination strategies should be tailored in the elderly.³¹

Another group at increased risk of mordidity and mortality from influenza are infants and children. The strategies for their protection and arising problems are discussed by Principi and Esposito.³²

In pregnant women, Nunes and Madhi showed that receipt of influenza vaccine during pregnancy was associated with decreased risk of laboratory-confirmed influenza infection in the infants.³³ Ellingson et al. documented that pregnant women use the Internet for information about vaccines, but they still value input from their providers.³⁴

Dini et al. explaned why the topic of influenza vaccination among HCWs is challenging, full of ethical issues.³⁵ Mandatory policies are under debate in several countries. High-quality studies would help policy-makers and stake-holders to shape evidence-based initiatives and programs to improve the control of influenza.

Overall, all these studies have highlighted that influenza vaccination has been considered the best measure to limit influenza incidence and to reduce the disease-related medical, social and economic consequences.

Therapy

Although prevention through vaccination represents the best way to control influenza, studies on therapy are ongoing.

Fedson demonstrated that combinations of generic drugs like statins and angiotensin receptor blockers might be used to treat the host response to infection. He highlighted that clinicians might have to undertake clinical trials in patients hospitalised with seasonal influenza, pneumonia and sepsis in order to show convincingly whether treating the host response would work.³⁶

Berry et al. presents the pros and cons of monoclonal versus polyclonal antibody therapy for influenza.³⁷

Conclusions

Despite the availability of relatively effective prophylactic measures, influenza remains one of the most important infectious disease threats to the human population. One hundred years since the influenza pandemic, seasonal influenza epidemics infect every year up to 30% of the population, a significant portion of the ill are hospitalized, and more than a marginal number die. We hope that this centenary issue will highlight the medical, social and economic burden of influenza and the importance of high rates of vaccination coverage in order to reduce influenza-related complications and mitigate the risk of further pandemics.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.