Influenza is a seasonal disease. It fluctuates in a very typical manner, and probably has for centuries, but certainly for decades since it’s been monitored.
Influenza-like illness (ILI) refers to the clinical condition caused by various respiratory pathogens but is typically driven by the influenza virus. ILI rates rise above baseline between November and February and decrease by March and April in the Northern Hemisphere. Within that narrow window, the timing of peak infection varies as does the yearly mortality, both driven by changes in the circulating flu strains.
Seasonal vaccine effectiveness
Likewise, vaccine efficacy varies widely from year to year (see Figure 1). Subtle or significant changes in the influenza virus itself dictate what the efficacy will be for any vaccine. For example, in both the 2004 and the 2014 seasons, the efficacy of the vaccine was quite low due to shifts in the H3N2 circulating strains compared to the strain used in the vaccine. In 2004, the A/Fujian strain was chosen for the vaccine, but unrelated strains actually circulated that year, resulting in lower vaccine efficacy. In 2014, the H3N2 strain, A/Texas, was selected for the Northern Hemisphere vaccine. Again, the circulating H3N2 strains that year did not match A/Texas, so vaccine efficacy decreased.
Influenza structure
There are eight genes in influenza. Two of them are represented in segments four and six, the hemagglutinin (HA) and neuraminidase genes (NA), respectively. Hemagglutinin is responsible for entry of the virus into cells via sialic acid residues. Neuraminidase is responsible for releasing the virus from infected cells in combination with the hemagglutinin antigen. There are 18 serotypes for hemagglutinin and 11 serotypes for neuraminidase. Because they are present on the surface of the virus, these are the most immunogenic antigens. Vaccine candidates are chosen based on the HA thought most likely to be prevalent in the next season.
Antigenic drift vs. shift
Two biological activities dictate how effective an influenza vaccine will be.
The first is antigenic drift, in which mutations in the hemagglutinin and neuraminidase genes result in small changes to those proteins. These changes in influenza occur as it goes through its normal stage of infection among multiple species (humans, pigs, birds), making those antigens unrecognizable by antibodies from previous influenza exposures.
Antigenic shift is a more dramatic change in which major changes occur in influenza A viruses that result in a new hemagglutinin or a new combination of hemagglutinin and neuraminidase proteins in a virus infecting humans. The most well-known example of antigenic shift is the Spanish flu of 1918, in which there was little or no cross protection.
Although influenza changes from year to year, we still rely on the prediction of the strains that will be circulating in the upcoming year to select for vaccine production.
Because of the difficulty of this process, there is an effort to find alternative solutions to enhance the yearly efficacy of the vaccine.
Traditional vaccine production
For now, twice a year, in February for the upcoming Northern Hemisphere season, and in September for the upcoming Southern Hemisphere season, the strains to be used in the vaccines are selected based on the consensus of experts.
The HA and NA genes that are identified are inserted either by reverse genetics or through re-assortant technology into viral backbone genes, typically the A/Puerto Rico/8/34 strain, that are adapted for growth in eggs. That engineered virus becomes the candidate vaccine virus (CVV). The CVV is then made available, from either the World Health Organization (WHO) or the Centers for Disease Control and Prevention (CDC) for use in either egg-based vaccine production or cell culture-based systems.
Next-generation vaccines
Driven by both the need to adapt to new strains every year as well as to develop production techniques that are more efficient, new- generation vaccines have either been approved and are on the market or are still in the investigation stage and in various phases of clinical trials.
Medicago is in phase 3 clinical trials with a VLP (virus-like part...
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