Comparing the Effectiveness of Influenza Vaccines: Subunit Vaccine vs. Split-Virion Vaccine

Introduction: The Importance of Influenza Vaccination and Vaccine Types

Influenza remains a significant global public health threat, particularly affecting older adults aged 65 and above and individuals with underlying health conditions. Vaccination is the most effective preventive measure against influenza. However, vaccines produced using different manufacturing processes may vary in their clinical effectiveness. This article compares the clinical effectiveness of two common inactivated influenza vaccines: the split-virion vaccine and the subunit vaccine, based on a prospective study involving adults aged 50 and older.

Background: Understanding the Two Vaccine Types

Both vaccines start similarly — influenza viruses are cultured in pathogen-free eggs and then treated with detergents to disrupt the viral envelope. The key difference lies in subsequent purification steps.

• Split-virion vaccine: Undergoes minimal purification, retaining more internal viral proteins such as nucleoproteins, polymerases, and matrix proteins. This results in a higher total protein content and typically a stronger reactogenicity (mild local or systemic reactions after vaccination).
• Subunit vaccine: Subjected to further purification to remove internal core proteins, preserving primarily surface proteins such as hemagglutinin (HA). This process reduces reactogenicity, which was a primary motivation for its development.

Historically, because both vaccines contain similar amounts of hemagglutinin and generate comparable antibody responses measured by hemagglutination inhibition (HAI) assays, their protective effects were considered equivalent. However, recent research suggests that antibody titers alone may not fully predict protection. Cellular immune responses, particularly T cell responses targeting internal viral proteins, may play a crucial role in protection against influenza — a potential explanation for differences in vaccine effectiveness.

Why Focus on Older Adults?

Aging weakens the immune system, diminishing antibody responses to vaccination. However, cellular immunity — especially CD8+ T cell responses against internal viral proteins — remains important for viral clearance and reducing disease severity in older adults. Since split-virion vaccines retain more internal proteins, they are hypothesized to better stimulate cellular immunity, making them potentially more suitable for elderly populations. Yet, direct clinical evidence has been limited until now.

Study Design: A Head-to-Head Comparison

To assess the clinical effectiveness difference, researchers employed a test-negative case-control design, a widely accepted method for vaccine effectiveness evaluation.

• Participants: Adults aged 50 and older from Nashville, Tennessee, presenting with acute respiratory illness or unexplained fever during three influenza seasons (2008-2009, 2010-2011, and 2011-2012). The 2009-2010 season was excluded due to the late introduction of the H1N1 pandemic vaccine and unstable data.
• Data Collection: Symptoms, smoking status, vaccination history (including timing, manufacturer, batch number), and underlying conditions (e.g., diabetes, heart disease, immunosuppression) were documented. Confirmatory laboratory testing was done using RT-PCR to identify influenza-positive and influenza-negative individuals.
• Vaccine Verification: Vaccination status was confirmed at least two weeks prior to symptom onset and validated through healthcare providers, pharmacies, and employers to avoid recall bias.
• Analysis: Logistic regression was used to calculate vaccine effectiveness (VE) as (1 – adjusted odds ratio) × 100%, adjusting for age, sex, race, smoking, underlying conditions, influenza season, and healthcare setting. Sensitivity analyses included multiple imputations for missing manufacturer data.

Results: Split-Virion Vaccine Demonstrates Superior Effectiveness

Among 840 participants, complete data were available for 539 individuals (471 influenza-negative controls and 68 influenza-positive cases).

• Demographics: Influenza-positive participants were younger on average (median age 61.3 vs. 65.9 years) and more likely to be unvaccinated or have received the subunit vaccine. Influenza cases were more frequently seen in emergency or outpatient settings.
• Influenza Incidence: The incidence of influenza was significantly lower in those vaccinated with the split-virion vaccine (5.4%) compared to the subunit vaccine group (12%).
• Vaccine Effectiveness: The split-virion vaccine showed an overall effectiveness of 77.8% (95% CI: 58.5%-90.3%), significantly higher than the subunit vaccine’s 44.2% (95% CI: -11.8%-70.9%), where the confidence interval included zero, indicating a less certain protective effect. The difference in effectiveness between the two vaccines was 33.5% (95% CI: 6.9%-86.7%), statistically significant.

Subgroup analyses by age, influenza season, and virus type confirmed the split-virion vaccine’s advantage across groups. Notably, in those aged 65 and older, the split-virion vaccine’s effectiveness was 74.0% versus 32.1% for the subunit vaccine. The split-virion vaccine also showed strong protection against both H1N1 and influenza B viruses.

Discussion: Why Does the Split-Virion Vaccine Perform Better?

The enhanced effectiveness of the split-virion vaccine likely stems from its ability to stimulate stronger cellular immune responses due to preserved internal viral proteins, which are absent in subunit vaccines.

Studies have shown that T cell responses targeting internal proteins (e.g., nucleoproteins) correlate with protection against influenza, especially in older adults. For example, markers of cellular immunity like IFN-γ secretion and granzyme B levels better predict protection than antibody titers alone.

Differences from previous European studies, which found no significant vaccine effectiveness difference, may relate to study populations (inpatient vs. outpatient), vaccine brands used, and sample sizes.

Other contributing factors might include differences in neuraminidase (NA) content, a viral protein involved in reducing virus spread and symptom severity, which is not standardized across vaccines. The split-virion vaccine may contain more NA, enhancing protection, especially in seasons with poor vaccine-virus strain matches.

Limitations and Future Directions

Limitations include:

• Data from a single geographic area and limited influenza seasons, potentially limiting generalizability.
• Predominant use of a single subunit vaccine brand may not reflect all subunit vaccines.
• Focus on short-term clinical outcomes without assessment of long-term protection or mortality impact.

Future research should expand to diverse populations and seasons, evaluate multiple vaccine brands, and investigate the role of internal viral proteins and cellular immunity in protection, guiding vaccine development.

Implications for Public Health and Clinical Practice

For adults aged 50 and older, especially those with underlying conditions or advanced age, the split-virion influenza vaccine (such as standard-dose Fluzone) may offer superior protection. However, vaccination remains crucial regardless of vaccine type, as individual immune status and virus strain match influence effectiveness.

Clinicians should tailor vaccine recommendations to patient characteristics and ensure accurate vaccination records, including manufacturer and batch details, to support ongoing research and vaccine safety monitoring.

Reference

Talbot HK, Nian H, Zhu Y, Chen Q, Williams JV, Griffin MR. Clinical effectiveness of split-virion versus subunit trivalent influenza vaccines in older adults. Clin Infect Dis. 2015 Apr 15;60(8):1170-5. doi: 10.1093/cid/civ019. Epub 2015 Feb 18. PMID: 25697739; PMCID: PMC4447778.