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  1. Biologics Research Projects

Impact of Immunity Induced by Viral and DNA Products

Principal Investigator: Suzanne L. Epstein, PhD
Office / Division / Lab: OTAT / DCGT / GTIB

General Overview

Influenza causes high rates of serious illness and deaths each year in the US and around the world. Current influenza vaccines depend upon surveillance of human infections around the world, selection of predominant strains, and production of new vaccines, a time-consuming process with limited capacity. New strategies are needed to control seasonal influenza, unexpected influenza outbreaks, avian influenza viruses such as H5N1, and pandemics such as the one caused by H1N1 in 2009. The goals of strategies would be to slow virus spread in the community and to reduce serious illness, hospitalization, and deaths.

This research program studies new approaches to influenza control that would work regardless of which influenza virus strain emerges. We study experimental "one-size-fits-all" vaccines that could be available off the shelf. They could be rapidly deployed to help control an emerging influenza virus that differs from available conventional vaccines. The new vaccines are designed to protect by stimulating the immune system to target those viral proteins that are similar ("conserved") among all influenza A viruses. This is intended to reduce the severity of disease and the spread of infection during the delay until a strain-match vaccine against the new influenza virus can be produced.

The vaccine candidates include plasmid DNA (small rings of DNA derived from bacteria) or adenovirus (a type of non-replicating virus used to express vaccine proteins in the recipient) modified to express influenza proteins, as well as weakened influenza viruses similar to those used in a current vaccine. We analyze the immune responses as well as protection against infection. Experimental models include mice and also ferrets, an animal in which influenza can spread and cause disease similarly to the way it does in humans. We have found that the experimental vaccines can protect against influenza infections that are lethal to unvaccinated animals, and that they protect against a broad range of virus strains including highly pathogenic H5N1 (bird flu). Most recently we have studied a single dose of vaccine given intranasally, and found protection as early as three weeks and as late as 10 months after vaccination.

We are also conducting a study of the possible role of broadly cross-protective immunity in susceptibility to disease during the 2009 pandemic.

FDA regulates two major categories of products based on viruses and plasmid DNA: vaccines and also gene therapy products to treat diseases that are currently untreatable. In the case of vaccines, immune responses are desirable for protection, and we need to identify the most effective responses. In the case of gene therapy, immune responses generated by a first treatment can stimulate an immune response that can block the activity of repeat treatment. Understanding the immune responses induced by vaccines and gene therapy products during laboratory studies in animals and during clinical studies in humans can help scientists design ways to make the products safer and more effective, and will also improve the ability of FDA regulators to make decisions about these products.

Scientific Overview

Control of influenza by vaccination is made difficult by the rapid evolution of the viral glycoproteins hemagglutinin and neuraminidase. This lab explores new approaches to influenza A vaccination that provide broad protection (heterosubtypic immunity) and are not based on strain-matching. Thus, protection does not depend on predicting which strain or even subtype of influenza will circulate. Broad cross-protection is seen in a variety of animal models: mice, ferrets, chickens, pigs, and cotton rats. It often permits low-grade infection, but reduces morbidity, mortality, and virus shedding. The experimental vaccines we study are intended to fill the gap when conventional vaccines are not available, are insufficient in supply, or are a poor match for the circulating virus. Protection could be supplemented by strain-matched vaccines, once available.

We have compared a variety of vaccination strategies in mice for potency of induction of cross-protection. The vaccine candidates include cold-adapted (ca) influenza viruses, as well as plasmid DNA and recombinant adenoviruses (rAd) expressing conserved antigens nucleoprotein (NP), matrix-2 (M2), or A/NP+M2. We have used DNA prime-viral boost strategies, as well as single agent vaccinations. The most potent crossprotection is seen with mucosal administration of viral vaccines at the site of infection (intranasal route), whether for a viral vaccine alone or as the viral boost after DNA priming. These protocols result in survival and greatly reduced symptoms, after challenge infections that are lethal to controls. They give stronger IgA responses, greater and more long-lasting virus-specific activated T-cell responses in the lung, and better protection against morbidity following challenge. Priming increases the potency of protection, but rAd alone is effective. A single-dose of A/NP+M2 rAd given intranasally provided protection as early as 2 weeks and as late as 10 months post-immunization. This vaccination protected mice against lethal challenge with H1N1, H3N2, and H5N1 viruses. The immune response measures in mice that differ among vaccinations provide candidate immune correlates for further study.

We have also studied vaccination in ferrets, an animal model resembling human influenza with regard to virus spread and symptoms. In addition, these animals are outbred and thus genetically diverse. Prime-boost vaccination with either mucosal and parenteral rAd boosting protected ferrets from lethal H5N1 challenge. Additional regimens are under study.

This program has also included epidemiological analysis to look for evidence of human heterosubtypic immunity. Archival records from the 1957 pandemic suggested the possibility of such protection. We are now conducting a study of the possible role of broadly cross-protective immunity in susceptibility to disease during the 2009 pandemic.


PLoS One 2019 Apr 15;14(4):e0215321
The effect of respiratory viruses on immunogenicity and protection induced by a candidate universal influenza vaccine in mice.
Rowell J, Lo CY, Price GE, Misplon JA, Crim RL, Jayanti P, Beeler J, Epstein SL

Am J Epidemiol 2018 Dec 1;187(12):2603-14
Universal influenza vaccines: progress in achieving broad cross-protection in vivo.
Epstein SL

Vaccine 2018 Aug 6;36(32 Pt B):4910-8
Reduction of influenza virus transmission from mice immunized against conserved viral antigens is influenced by route of immunization and choice of vaccine antigen.
Price GE, Lo CY, Misplon JA, Epstein SL

Vaccine 2018 Feb 8;36(7):1008-15
Conventional influenza vaccines influence the performance of a universal influenza vaccine in mice.
Rowell J, Lo CY, Price GE, Misplon JA, Epstein SL, Garcia M

Open Forum Infect Dis 2017 Feb 12;4(2):ofx023
Surveillance study of influenza occurrence and immunity in a Wisconsin cohort during the 2009 pandemic.
Lo CY, Strobl SL, Dunham K, Wang W, Stewart L, Misplon JA, Garcia M, Gao J, Ozawa T, Price GE, Navidad J, Gradus S, Bhattacharyya S, Viboud C, Eichelberger MC, Weiss CD, Gorski J, Epstein SL

Science 2016 Nov 11;354(6313):706-7
First flu is forever.
Viboud C, Epstein SL

PLoS One 2016 Apr 7;11(4):e0153195
Age dependence of immunity induced by a candidate universal influenza vaccine in mice.
García M, Misplon JA, Price GE, Lo CY, Epstein SL

Gene Ther 2015 Oct;22(10):781-92
Enhanced T cell activation and differentiation in lymphocytes from transgenic mice expressing ubiquitination-resistant 2KR LAT molecules.
Rodriguez-Peña AB, Gomez-Rodriguez J, Kortum RL, Palmer DC, Yu Z, Guittard GC, Wohlfert EA, Silver PB, Misplon JA, Sommers CL, Feigenbaum L, Epstein SL, Caspi RR, Belkaid Y, Restifo NP, Samelson LE, Balagopalan L

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