Influenza infection in human host: challenges in making a better influenza vaccine

ABSTRACT

Influenza is a ubiquitous infection with a spectrum ranging from mild to severe. The mystery regarding such variability in the clinical spectrum has not been fully unravelled, although a role for the complex interplay among virus characteristics, host immune response and environmental factors has been suggested. Antivirals and current vaccines have a limited role in prophylaxis and treatment because they primarily target surface glycoproteins which undergo antigenic/genetic changes under host immune pressure. Targeting conserved internal proteins could lead the way to a universal vaccine which can be used against various types/subtypes. However, this is on the distant horizon, so in the meantime, developing improved vaccines should be given high priority. In this review, we discuss where the current influenza research stands in terms of vaccines, adjuvants, and how we can better predict the vaccine strains for upcoming influenza seasons by understanding complex phenomena which drive the continuous antigenic evolution.

KEYWORDS:

• Influenza
• innate immune response
• adaptive immune response
• heterosubtypic immunity
• vaccine mismatch
• adjuvants
• universal vaccine
• influenza proteins
• antigenic sites
• antigenic evolution

Financial and competing interests disclosure

PA Tambyah has received research support from Baxter, ADAMAS, MerLion Pharmaceuticals, Sanofi Pasteur, Fabentech and Invisagen; and honoraria from Novartis and Astra Zeneca. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Influenza is a highly contagious, acute respiratory tract illness with spectrum ranging from mild infection to life threatening disease in immunocompromised/immunosuppressed individuals.

• Influenza occurs mainly in winters in temperate regions but has no well-defined seasonality in tropical regions with influenza present all-year-around and hypothesized to be potentially responsible for the seeding virus in temperate regions.

• Antivirals have limited usefulness in controlling influenza as they only modestly reduce the time to first alleviation of symptoms, have side effects, and antiviral resistance has been on the rise.

• Vaccine preventable disease but vaccine mismatch is a major challenge with currently available vaccines when the circulating strains do not match with the vaccine strains due to antigenic drift necessitating repeated reformulation of vaccine.

• Current vaccine selection process rides on the assumption that an antigenically dominant strain is necessarily going to remain in a position of dominance during the next flu season [81]. It is therefore imperative to unravel the antigenic and genetic evolution of widely circulating subtypes in order to be able to better predict antigenic drift at key positions in the HA1 protein and hence make better vaccines.

• Prevention is the key so the vaccine efficacy needs to be improved with the use of adjuvants which can provide boost to immune response mediated by inactivated vaccines by stimulating nonspecific immune response, and currently, various adjuvants are undergoing clinical trials with M59 being the most advanced in these trails.

• Further research is needed in exploring ways to boost the innate immune response to augment the currently available vaccines as well as to better predict the dominant influenza strain in making recommendations for the trivalent/quadrivalent inactivated vaccines currently in clinical use.

• A universal vaccine targeting conserved internal proteins can provide heterosubtypic immunity and hence broad protection against various types, subtypes, novel, and drift strains.

• A universal vaccine with universal influenza immunization coverage seems like the ideal strategy to fight influenza illness burden; however, it seems to be some years away, possibly in the next 5–10 years.