Navigating the Complex Terrain of Influenza Vaccine Strain Selection

Quadrivalent Influenza Vaccines

All influenza vaccines available in the United States are now quadrivalent. These seasonal, quadrivalent influenza vaccines are specifically designed to offer protection against four distinct influenza viruses, encompassing two influenza A strains and two influenza B strains. These selected strains are anticipated to be most prevalent and cause illness during the upcoming flu season. 

In the past, flu vaccines were crafted to guard against three specific flu viruses: influenza A(H1N1), influenza A(H3N2), and a single influenza B virus. Introducing a second influenza B virus from a different lineage was intended to broaden the scope of protection against prevalent flu viruses. Well-known brand names for these vaccines include AFLURIA, Fluarix, FluLaval, Flucelvax, Fluzone, and FluMist.

Safety Profile Considerations

Flu vaccines that target four flu viruses exhibit a safety profile comparable to seasonal flu vaccines designed for three viruses, with predominantly mild side effects. Like all seasonal flu vaccines, various organizations and regulatory agencies monitor these vaccines annually for safety and effectiveness.

In the US, the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA) play key roles in monitoring the safety of vaccines. These organizations continuously collect and analyze vaccine safety data through the Vaccine Adverse Event Reporting System (VAERS) and the Vaccine Safety Datalink (VSD).

Vaccine Strain Monitoring and Selection

The meticulous selection of vaccine components involves evaluating flu viruses' prevalence, spread, and effectiveness from the previous season. As one of the World Health Organization (WHO) Collaborating Centers, the CDC plays a crucial role by contributing its global surveillance data to inform recommendations.

Since 1952, global influenza surveillance has been carried out through the WHO's Global Influenza Surveillance and Response System (GISRS), which now includes institutions in 129 WHO Member States.

GISRS — a network of 144 national influenza centers across 114 countries — continuously monitors flu viruses worldwide. Biannual consultations, organized by WHO with GISRS directors and key stakeholders, review surveillance, laboratory, and clinical studies. The recommendations from these meetings guide the composition of flu vaccines for the Northern and Southern Hemispheres.

CDC's Influenza Division conducts year-round surveillance, identifies flu viruses through global surveillance activities, and prepares candidate vaccine viruses (CVVs). The Division actively participates in WHO vaccine consultation meetings, contributing crucial data for strain recommendations. Ultimately, the FDA's Vaccines and Related Biological Products Advisory Committee (VRBPAC) makes the final decision for domestic flu vaccines based on the information presented by the CDC.

Several factors influence the selection of vaccine strains, ranging from epidemiologic and genetic data to antigenic properties and evolutionary analysis. Genetic sequencing of flu viruses allows scientists to monitor changes in their genomes, while antigenic characterization assesses the ability of antibodies to neutralize circulating viruses. Human serology studies, evolutionary analysis, and vaccine effectiveness studies also contribute to the comprehensive understanding needed for strain selection.

Challenges in Strain Selection

Influenza viruses are notorious for their ability to undergo frequent genetic changes, a characteristic that poses a significant challenge in the annual vaccine strain selection. The viruses' genomes constantly evolve, necessitating a thorough understanding of their genetic makeup.

CDC's continuous genetic characterization of circulating flu viruses plays a pivotal role in this regard. Through genetic sequencing, scientists monitor the changes in viral genomes throughout the year, helping anticipate how well vaccines and antiviral drugs will work against these mutating viruses.

Sometimes, chosen strains may become less effective due to significant viral changes after selection. The strain selection process is a delicate balance between anticipating virus evolution and producing an effective vaccine throughout the upcoming flu season.

Antigenic data, focusing on the molecular structures on the virus surface recognized by the immune system, guides the selection of vaccine strains. Hemagglutinin and neuraminidase are the major antigens triggering the immune response. Ferret antisera testing, a critical component of antigenic characterization, involves infecting ferrets with a flu virus to raise antibodies. If these antibodies effectively neutralize circulating flu viruses, the selected vaccine virus is considered antigenically similar, providing a level of confidence in its protective efficacy.

Recognizing the diverse immune responses in humans due to varying pre-existing antibodies from prior infections and vaccinations, the CDC employs human serology studies. These studies involve collecting blood samples from people before and after flu vaccination and testing for antibodies. The results help gauge how well antibodies elicited from vaccination can recognize and neutralize circulating flu viruses. This human-centric approach enhances the accuracy of strain selection by considering the nuanced complexities of individual immune responses.

The evolutionary analysis of flu viruses considers their fitness advantages and disadvantages, influencing their competition with other circulating flu viruses. Through predictive flu forecasts, scientists anticipate the most likely viruses to circulate and predominate during the upcoming season. This integrated data approach aids in making informed decisions about the strains that should be included in the vaccines, aligning with the dynamic nature of influenza viruses.

Vaccine effectiveness studies, conducted in real-world conditions, assess how well available flu vaccines work against circulating viruses. These studies consider various outcomes, such as preventing illness resulting in hospitalization or death. The antigenic similarity between vaccine viruses and circulating viruses significantly influences the benefits of vaccination. This holistic approach ensures a comprehensive understanding of vaccine effectiveness, considering both virus and host factors.

Seasonal Vaccine Production

Private-sector manufacturers initiate the vaccine production process once the VRBPAC finalizes strain recommendations based on WHO recommendations and domestic flu data. Given the time-sensitive nature of vaccine production, these decisions are typically made in February or March, well before the start of the flu season. 

However, because vaccine production timelines are lengthy — taking at least six months — some manufacturers may start growing viruses for production even before official recommendations, allowing for more doses. This extended period ensures that sufficient doses are produced before the flu season begins.

Vaccine Production Challenges

Producing quadrivalent influenza vaccines involves navigating several challenges rooted in the dynamic nature of the influenza virus. Traditional egg-dependent production methods can be time-consuming, and certain strains, like A(H3N2), may not grow efficiently in eggs, limiting scalability and production efficiency.

Ensuring vaccine yield and scalability is crucial to meeting global demand, especially during periods of heightened need. Strict quality control measures are essential to maintaining the purity and potency of each virus strain in the vaccine. However, the seasonal variability of influenza viruses poses an ongoing challenge, requiring constant adaptation of vaccine formulations to address changes in circulating strains.

Addressing the broader issues of antigenic drift and shift, where influenza viruses undergo changes in surface proteins, further complicates the formulation of effective vaccines.

In addition, navigating the complex regulatory compliance landscape adds another layer of difficulty, as meeting stringent safety, efficacy, and quality standards is essential.

Storage and distribution logistics must also be carefully managed to ensure the vaccine remains stable and effective, particularly in regions with limited access to refrigeration. Although storage temperatures for influenza vaccines can vary depending on the specific formulation of the vaccine, most influenza vaccines are typically stored at refrigerated temperatures between 35 and 46 °F (2 and 8 °C).

Overcoming these challenges demands continuous research, innovation, and collaboration among scientists, manufacturers, and regulatory agencies to enhance the efficiency and effectiveness of quadrivalent influenza vaccine production.

Overall, the annual selection of influenza vaccine strains is a critical process that has evolved to address the dynamic nature of the influenza virus. The shift to quadrivalent vaccines, offering protection against four flu strains, represents a strategic response to enhance efficacy and align with anticipated viral prevalence.

To overcome selection and production challenges, ongoing collaboration and innovation are vital for ensuring the efficiency and accessibility of quadrivalent influenza vaccines. Collective effort remains essential in the global endeavor to combat influenza and safeguard public health.