Jeffrey Almond on vaccine development

Dr. Jeffrey Almond began his career as an academic virologist studying influenza virus, then moved to poliovirus. He made major contributions to our understanding of the molecular basis of poliovirus attenuation and reversion to virulence. After 20 years in academics he moved to Sanofi Pasteur, where he is currently Vice President, discovery research and external R&D.

I interviewed Jeffrey Almond, Ph.D., in Manchester UK at the 2013 meeting of the Society for General Microbiology. We spoke about the eradication of poliovirus, challenges in making a universal influenza vaccine, a dengue virus vaccine developed by Sanofi Pasteur, and moving from academia to industry.


Universal influenza vaccines

The need to re-formulate the influenza virus vaccine in response to viral antigenic drift and shift makes for complex logistics of vaccine production and administration. Surveillance programs must be conducted each year to identify strains that are likely to predominate and cause disease. Wouldn’t it be simpler if a single vaccine could be developed that would confer protection against a broad range of viral strains? Results from the past year suggest that such a vaccine might be closer than previously thought.

The influenza viral HA protein consists of a globular head atop a stem that is embedded in the virion membrane (figure). Most protective antibodies are directed against the head of the HA molecule. Rare antibodies that block infection with a broad range of influenza virus strains are directed toward the conserved stalk of the viral surface glycoprotein HA. This observation was taken a step further by showing that sequential immunization with different viral HAs, or with HA lacking the globular head, induce broadly neutralizing antibodies. Peter Palese discussed these approaches on TWiV #102.

In another approach, neutralizing antibodies have been induced by immunizing first with plasmid DNA, followed by a boost with recombinant adenovirus encoding the HA protein. Mice were immunized first with plasmid DNA encoding an H1 HA from the 2006-2007 influenza season, then boosted with a recombinant adenovirus encoding the same HA protein. Sera from immunized mice neutralized strains of H1N1 influenza virus dating to 1934, as well as H2N2 and H5N1 viruses. When inoculated with a 1934 H1N1 virus, immunized mice were protected from lethal disease. Immunization of ferrets with a similar regimen also protected these animals from lethal disease. Broadly neutralizing antibodies were elicited in nonhuman primates by this prime-boost regimen.

Both the plasmid DNA and the recombinant adenovirus encoded the full-length HA protein, with both the globular head and fibrous stem. However, the broadly neutralizing and protective antibodies were directed against the stem. Anti-HA stem antibodies were also identified in monkeys that had been immunized with the prime-boost combination.

Why doesn’t the seasonal influenza vaccine elicit broadly neutralizing antibodies? These vaccines induce antibodies that almost exclusively bind the variable head of the HA, not the conserved stem. The reason probably lies in how the vaccines are prepared: virions are inactivated by treatment with detergent and formaldehyde, a process that destroys the particle. Consequently, the vaccine contains mainly HA and NA and not other components that can help shape a more diverse antibody repertoire. In contrast, it is known that plasmid-based priming can stimulate B cells to produce a more diverse set of antibodies.

The strategy of priming with plasmid DNA followed by boosting with recombinant adenovirus will likely be evaluated in clinical trials for the ability to protect against natural infection with influenza virus. The possibility of a broadly protective influenza virus vaccine that would be taken perhaps every 10-20 years is rapidly becoming a reality.

Wang TT, Tan GS, Hai R, Pica N, Petersen E, Moran TM, & Palese P (2010). Broadly protective monoclonal antibodies against H3 influenza viruses following sequential immunization with different hemagglutinins. PLoS pathogens, 6 (2) PMID: 20195520

Wei CJ, Boyington JC, McTamney PM, Kong WP, Pearce MB, Xu L, Andersen H, Rao S, Tumpey TM, Yang ZY, & Nabel GJ (2010). Induction of broadly neutralizing H1N1 influenza antibodies by vaccination. Science (New York, N.Y.), 329 (5995), 1060-4 PMID: 20647428

Headless HA: Universal influenza vaccine?

A serious shortcoming of current influenza virus vaccines is the need to reformulate them every year or two as the virus undergoes antigenic drift. Many virologists have been captivated by the idea of a more universal vaccine that would endure longer, perhaps a decade or more. The identification of a conserved domain in the stalk region of the viral HA protein that gives rise to antibodies that block infection by 10 HA subtypes was a step in this direction. The next phase in the development of a new vaccine, the production of an antigen that confers broader protection, has been achieved using an HA molecule lacking the globular head.

The vast majority of antibodies that block influenza virus infection are directed against the globular head of the HA, the protein essential for attachment to and entry into cells. Unfortunately, the HA head undergoes significant antigenic variation. The HA stalk is more conserved, but this portion of the molecule is likely to be masked by the globular head and therefore not readily recognized receptors on antibody-producing B cells.

To make the HA stalk more accessible, an altered molecule was designed that lacks the globular head. To test whether this protein could give rise to broadly neutralizing antibodies, mice were immunized first with plasmid DNA encoding the truncated protein, and then with virus-like particles bearing the headless HA. When mice were immunized with headless HA from a 1934 H1N1 strain, all survived after intranasal challenge with the homologous virus. The sera from these mice showed broader reactivity against H2N2, H5N1, and 2009 pandemic H1N1 viruses than sera from mice immunized with full-length HA.

While the observations are encouraging, they are not unequivocally positive. For example, it was not possible to demonstrate neutralizing antibodies in sera from mice immunized with headless H1 or H3 HA proteins. Furthermore, the ability of headless H3 HA to protect mice from challenge infection was not determined. Nevertheless, the results show that vaccination with a headless HA confers protection against antigenically diverged influenza virus strains. The authors conclude “Through further development and testing, we predict that a single immunization with a headless HA vaccine will offer effective protection through several influenza epidemics.” Not an influenza vaccine for life, but perhaps more enduring than those available today.

Steel, J. (2010). An Influenza Virus Vaccine Based on the Conserved Hemagglutinin Stalk Domain mBio DOI: 10.1128/mBio.00018-10