Figure 1. Influenza Remains a Threat to the US population (Adapted from CDC, 2022)
Influenza, also known as the common flu, infects approximately 8% of the United States population annually, leading to 140,000-710,000 hospitalizations and 12,000-52,000 deaths from 2010 to 2020 (CDC, 2023) (CDC, 2022). Influenza is becoming more prevalent, causing more infections, hospitalizations, and deaths (see Figure 1). Those most at risk include the very young, the elderly, and those with chronic medical conditions (Schmidt & Lapuente, 2021). Common symptoms of influenza include fever, cough, sore throat, runny nose, and fatigue (CDC, 2023). An annual vaccine offers the best protection against influenza, however, this vaccine has drawbacks. A universal vaccine, while still under development, would largely alleviate these issues. For example, a universal vaccine would teach the immune system to protect against all strains of influenza, not just the strain that happens to be circulating during the flu season.
There are 4 distinct types of influenza genera that circulate: A (IAV), B (IBV), C (ICV), and D (IDV). IAV and IBV are most prevalent in human infections. IBV has a limited host range and strain diversity whereas IAV is constantly creating new lineages and subtypes. IAV alters through genetic drift, the exchange of gene segments among different IAV strands, and because its viral polymerase lacks proofreading activity, causing a backup of mutations. Therefore, IAV poses a greater risk for causing a pandemic. Influenza strains can be further classified by their glycoproteins: hemagglutinin (HA), which has 3 types– 1 (H1), 2 (H2), and 3 (H3) – and neuraminidase (NA) which has 2 types– 1 (N1) and 2 (N2). These antigens are highly variable among strains and no single vaccine offers full protection against them. The most devastating influenza outbreak in 1918, often dubbed the Spanish Flu, was caused by the H1N1 IAV that led to fifty million deaths worldwide (CDC, 2022). Most recently, in 2009, the H1N1 IAV, known as swine flu, swept the globe at an unprecedented rate due to airline travel. Additional influenza pandemics caused by IAV have appeared more and more frequently as our world becomes increasingly connected. Further, the coronavirus pandemic demonstrated the impact a pandemic may have on nearly every aspect of daily life. IAV remains a constant threat as it has the potential to become a pandemic once more.
Figure 2. History of Influenza A Virus Outbreaks (Adapted from Al Hajjar & McIntosh, 2010)
Vaccines are the best protection against influenza, however, current vaccines have many drawbacks. To develop the annual vaccine, scientists must first predict and identify which strain will dominate the flu season. Even if their predictions are correct, the vaccine efficacy (VE) will still be less than 70%. However, if their predictions are incorrect, the VE will be close to 0%. This process is also slow; it takes six months after an influenza outbreak to make a vaccine commercially available to the public. Existing influenza vaccines are imperfect and depend on strain-specific neutralizing antibodies, leaving them vulnerable to new strain mutations.
Figure 3. Varying Types of Influenza Vaccines (Adapted from Al Hajjar & McIntosh, 2010)
A universal influenza vaccine would alleviate many of these issues and offer broad immunity. While the annual vaccine’s VE depends largely on how the virus mutates over the duration of the flu season, a universal vaccine would develop protection against conserved parts of the influenza virion. To create a universal vaccine, scientists study the similarities across flu strains to isolate identical segments and then train the immune system to make protective antibodies. As early as 1965, Jerome Schulman and Edwin Kilbourne noticed that mice recovered from a prior H1N1 infection were partially protected against virus replication, mortality, and lung tissue damage after an H2N2 infection. Immune cells called T cells are crucial to this protection. In mice and humans, T cell responses are centered on internal virus proteins such as nucleoproteins, polymerases, and more. Other types of T cells are more diverse and can recognize surface proteins HA and NA. One study found IAV-specific T cell responses at a baseline of 43% in the study population and discovered that the presence of viral nucleoprotein-specific T cells significantly decreased the chance of developing a symptomatic IAV infection. Other studies have confirmed that T cells show a strong inverse correlation to symptom scores. Many of these studies with T cells have done well with animal models but not many have progressed to human clinical trials.
While a universal vaccine is still being developed, it will be extremely beneficial. Recent vaccines are not sufficient to protect the community against seasonal and pandemic influenza flu strains. A universal flu vaccine would solve many of the issues current vaccines present and would offer a higher VE. While they are still a work in progress, these vaccines have great potential and importance.
Works Cited