Preventing a ‘Twindemic’: Advances and Challenges in Flu and Covid-19 Vaccine Development
Kristen Marks, MD
Associate Professor of Medicine / Clinical Trials Unit Co-Director
Division of Infectious Disease / Weill Cornell Medicine
Influenza and Sars-Cov2 are two viruses whose stories are tied to major pandemics killing millions of people. Influenza and COVID-19 have a similar disease presentation, causing a wide range of respiratory disease from asymptomatic or mild through to severe disease and death, and both viruses are transmitted by droplets and fomites, making public health prevention measures essential to prevent the spread of disease.
Influenza A are negative-strand RNA viruses with a segmented genome encoding for 11 proteins. They further are classified based on the subtype of their surface glycoproteins, the hemagglutinin (HA) and the neuraminidase (NA). HA and NA are important for viral entry and release of new virus.These surface proteins, especially the HA, are strongly immunogenic. However, because of the characteristic segmented genomes and their error-prone RNA-dependent RNA polymerases, influenza viruses undergo antigenic shift and drift, which allow the evasion of the adaptive immune responses in a range of mammalian and avian species, including humans. Because of this ability, the development of highly efficacious, cross-reactive and long-lasting vaccines against influenza viruses has been challenging. Despite years of research, the effectiveness of current influenza vaccine ranges between 40 and 60 percent at best. All the influenza vaccine currently approved in the US are quadrivalent vaccines, and contain two strains of influenza A and 2 strains of influenza B. More common are killed vaccines that use virus grown in eggs or ,more recently, in cell culture. There is also an HA protein-only vaccine formulation. For older individuals, high dose or adjuvanted formulations have been developed. Live-attenuated influenza virus have shown not to be very effective in adults. More efforts are being focused on creating universal vaccines that will protect against multiple strains using several strategies including targeting conserved regions in the stem (an antigenically protected and conserved region) of the HA or expressing multiple HA and adding additional antigenic targets.
Some of the public health efforts through the years in planning for the next influenza pandemic and the research efforts for the development of a universal influenza vaccine have been instrumental for the rapid development of vaccines, when, approximately 100 years after the most lethal influenza pandemic, Covid-19 started its lethal march all over the world. Using the resources of the federal government and the US private sector, Operation Warp Speed (OWS) has worked to accelerate the testing, supply, development, and distribution of safe and effective vaccines. This process has been made possible by creating vaccine candidates using vaccine platforms that were developed for other diseases, using very large clinical trials with harmonized study design and a common external review monitoring board. Providing continuous safety and efficacy data to the FDA has also accelerated the approval process.
Six main vaccine candidates were chosen to enter phase 3 clinical trials. Two are mRNA vaccines that use a well-studied but not previously applied vaccine platform, two are adenovirus-based viral vector vaccines, and two use a protein plus adjuvant backbone. Clinical trials results were discussed.
References and readings
- https://www.cdc.gov/flu/vaccines-work/effectiveness-studies.htm
- Wei, CJ., et al.Next-generation influenza vaccines: opportunities and challenges. Nat Rev Drug Discov 19, 239–252 (2020).
- Krammer, F. SARS-CoV-2 vaccines in development. Nature 586, 516–527 (2020).
- https://www.defense.gov/Explore/Spotlight/Coronavirus/Operation-Warp-Speed/
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- Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. Engl. J. Med. 384, 403–416 (2021).