Influenza vaccine effectiveness against influenza A-associated hospitalization and severe in-hospital outcomes among adults in the United States, 2024-2025

During the severe 2024–2025 influenza season in the United States, vaccination significantly reduced the risk of influenza A-associated hospitalization and severe in-hospital outcomes, including ICU admission and death, among adults.

The Gist

Imagine the 2024–2025 flu season wasn't just a cold snap; it was a full-blown winter storm that lasted from November all the way to April. It was the worst flu season the U.S. has seen since before the pandemic. Two main "villains" were causing the trouble: Influenza A(H1N1) and Influenza A(H3N2). The H3N2 villain was particularly tricky because it had slightly changed its "costume" (antigenic drift), making it harder for our body's defenses to recognize it.

To see if the flu vaccine still worked as a shield against this storm, researchers from the CDC and 26 hospitals across the country launched a massive investigation called the IVY Network.

Here is the story of what they found, explained simply:

The Big Experiment: The "Test-Negative" Detective Game

Imagine a hospital emergency room. Doctors have two groups of patients:

1. The "Sick" Group: People who came in with bad breathing problems and tested positive for the flu.
2. The "Control" Group: People who came in with similar breathing problems but tested negative for the flu (they had something else, like a different virus or just a bad cold).

The researchers asked a simple question: "Who among these two groups had gotten the flu shot?"

If the vaccine works, you would expect to see far fewer vaccinated people in the "Sick" group compared to the "Control" group. It's like checking if people wearing raincoats are getting wet less often than those without them during a storm.

The Results: The Shield Held Up

The study looked at over 6,000 adults. Here is what the data revealed:

1. The Shield Against Getting Sick Enough to Go to the Hospital
The flu vaccine was about 40% effective at stopping people from getting sick enough to end up in the hospital.

• Think of it this way: If 100 unvaccinated people got the flu and ended up in the hospital, the vaccine would have saved about 40 of those people from needing that trip.
• Good news: This protection was pretty consistent whether the patient was young (18–49), middle-aged (50–64), or older (65+). It worked against both the H1N1 and the tricky H3N2 viruses.

2. The Shield Against the "Heavy Hitters" (Severe Outcomes)
This is where the vaccine really shined. Getting the shot didn't just prevent hospitalization; it acted like a reinforced bunker against the worst parts of the illness.

• Oxygen Support: It reduced the need for standard oxygen by 41%.
• ICU Admissions: It cut the risk of needing the Intensive Care Unit by 58%.
• Life-Saving Machines: It reduced the need for invasive machines (like ventilators) by 58%.
• Death: Most importantly, it reduced the risk of dying from the flu by 52%.

Analogy: If the flu is a car crash, the vaccine didn't always stop the car from hitting the tree (getting sick), but it definitely made sure the airbags deployed and the seatbelt held, preventing the crash from being fatal or requiring a trip to the trauma center.

The Nuances: Where the Shield Had Weak Spots

While the vaccine was a hero overall, it wasn't perfect for everyone:

• The "Immunocompromised" Group: For people with weakened immune systems (like those undergoing chemotherapy or with certain diseases), the study couldn't prove the vaccine prevented hospitalization. Their immune systems were like a castle with a broken gate; even with the vaccine's help, the virus could still get in. The researchers suggest these folks need extra help, like early antiviral medication, once they get sick.
• The "Older" Group vs. The "Tricky" Virus: Older adults (65+) had slightly less protection against the H3N2 virus compared to younger adults. This is likely because older people haven't seen this specific version of the virus since they were children, so their immune systems didn't have a "memory" of it to fight back quickly.
• Time Matters: The vaccine worked best if you got it 14 to 60 days before getting sick, but it still offered decent protection even if you got it months earlier.

The Bottom Line

During a very severe flu season where the virus was changing its disguise, the flu vaccine proved to be a powerful life-saver.

• It lowered the chance of ending up in the hospital.
• It drastically lowered the chance of needing a ventilator or dying.
• It worked for almost everyone, though people with very weak immune systems might need extra layers of protection.

The Takeaway: Think of the flu vaccine not as an invisible force field that makes you immune to the virus, but as a high-tech armor. It might not stop the arrow from hitting you, but it ensures that when it does, you survive the battle.

Technical Summary

1. Problem Statement

The 2024–2025 U.S. influenza season was historically severe, characterized by sustained elevated activity from November 2024 to April 2025, with roughly equal circulation of Influenza A(H1N1)pdm09 and A(H3N2). While A(H1N1) strains were antigenically similar to vaccine components, some circulating A(H3N2) viruses exhibited antigenic drift.

Previous literature suggests that VE against A(H3N2) is often reduced due to egg-adapted changes in vaccine production, antigenic drift, and "immune imprinting" (lack of early-life exposure to A(H3N2) in adults born before 1968). However, there is limited data on how VE differs specifically against severe in-hospital outcomes (e.g., ICU admission, mechanical ventilation, death) between A(H1N1) and A(H3N2) subtypes, particularly in older adults and immunocompromised populations. This study aimed to quantify VE against hospitalization and severe outcomes across these variables during a severe, mixed-subtype season.

2. Methodology

• Study Design: A multicenter, test-negative case-control study.
• Setting & Population: The Investigating Viruses in the Acutely Ill (IVY) Network, comprising 26 hospitals across 20 U.S. states.
  • Enrollment Period: October 1, 2024, to April 30, 2025.
  • Participants: Adults (≥18 years) hospitalized with Acute Respiratory Illness (ARI) defined by fever, cough, shortness of breath, hypoxemia, or new pulmonary findings.
• Case/Control Definitions:
  • Cases: Patients testing positive for influenza via local clinical testing and/or centralized RT-PCR.
  • Controls: Patients testing negative for influenza by both local and centralized RT-PCR.
  • Exclusions: Patients with SARS-CoV-2 or RSV coinfections (to minimize confounding), those with unknown vaccination status, or those vaccinated <14 days prior to illness onset.
• Virology: Nasal swabs underwent centralized RT-PCR. Positive influenza samples underwent Whole Genome Sequencing (WGS) to determine subtypes and subclades.
• Vaccination Status: Determined via electronic medical records, immunization information systems (IIS), and self-report. Vaccination was defined as receiving the 2024–2025 seasonal vaccine ≥14 days before illness onset.
• Statistical Analysis:
  • Multivariable logistic regression was used to calculate adjusted Odds Ratios (aOR).
  • VE Calculation: $VE = (1 - aOR) \times 100$.
  • Covariates: Age, sex, race/ethnicity, Census region, and enrollment month/year.
  • Outcomes: Primary outcome was influenza-associated hospitalization. Secondary outcomes included severe in-hospital events: standard oxygen therapy, non-invasive advanced respiratory support, invasive organ support (mechanical ventilation, renal replacement, vasopressors), ICU admission, and death.
  • Stratification: Analyses were stratified by age, immunocompetence, underlying conditions, time since vaccination, and influenza A subtype.

3. Key Results

Study Population:

• Total Analyzed: 6,109 patients (1,735 influenza cases, 4,374 controls).
• Virology: 1,113 cases had subtype data: 58% A(H1N1)pdm09 and 42% A(H3N2). No Influenza B was detected.
• Vaccination Rates: 34% of cases vs. 44% of controls were vaccinated ($p < 0.01$).

Vaccine Effectiveness (VE) Against Hospitalization:

• Overall VE: 40% (95% CI: 32%–47%).
• By Subtype:
  • A(H1N1)pdm09: 42% (95% CI: 30%–51%).
  • A(H3N2): 44% (95% CI: 30%–55%).
• By Age:
  • 18–49 years: 50% (95% CI: 31%–63%).
  • 50–64 years: 41% (95% CI: 25%–53%).
  • ≥65 years: 39% (95% CI: 28%–48%).
• By Immunocompetence:
  • Immunocompetent: 47% (95% CI: 39%–54%).
  • Immunocompromised: 7% (95% CI: -19%–28%; Not statistically significant).
• By Time Since Vaccination: VE remained consistent across intervals (14–59 days: 50%; 60–119 days: 40%; ≥120 days: 35%).

VE Against Severe In-Hospital Outcomes:
Vaccination significantly reduced the risk of all evaluated severe outcomes:

• Standard Oxygen Therapy: 41% (95% CI: 31%–50%).
• Non-invasive Advanced Respiratory Support: 38% (95% CI: 19%–52%).
• Invasive Organ Support: 58% (95% CI: 44%–69%).
• ICU Admission: 58% (95% CI: 47%–67%).
• Death: 52% (95% CI: 18%–71%).

Subtype-Specific Severe Outcomes:

• VE against severe outcomes was generally similar for A(H1N1) and A(H3N2), though estimates for A(H3N2) were slightly lower.
• Notably, VE against A(H3N2)-associated death and non-invasive support crossed the null (not statistically significant) in some stratifications, whereas A(H1N1) protection remained robust.
• In adults ≥65 years, protection against A(H3N2)-associated hospitalization was lower (35%) compared to A(H1N1) (40%), and VE against severe outcomes for A(H3N2) in this age group was less consistent.

4. Key Contributions

1. Severe Outcome Protection: Provides robust evidence that despite antigenic drift in A(H3N2), the 2024–2025 vaccine provided significant protection (>50%) against the most severe outcomes, including invasive organ support, ICU admission, and death.
2. Subtype Comparison: Offers granular data comparing VE between A(H1N1) and A(H3N2) for severe outcomes, confirming that while A(H3N2) protection is slightly lower, it remains substantial for most outcomes.
3. Immunocompromised Gap: Highlights a critical lack of measurable protection against hospitalization for immunocompromised patients (VE 7%, CI crossing zero), suggesting vaccination alone may be insufficient for this high-risk group and emphasizing the need for adjunctive therapies (e.g., early antivirals).
4. Age-Related Disparities: Reinforces the finding that adults ≥65 years have reduced VE against A(H3N2) compared to younger adults, likely due to immune imprinting and immunosenescence.
5. Durability: Demonstrated that VE remained consistent over time (up to >120 days post-vaccination), countering concerns of rapid waning during a prolonged season.

5. Significance and Limitations

Significance:

• The study validates the utility of seasonal influenza vaccination in preventing severe morbidity and mortality, even in a season with antigenic drift and high severity.
• It supports public health messaging that vaccination is crucial for reducing the burden on healthcare systems (ICU/ventilator usage) and preventing death, particularly in the general adult population.
• The findings underscore the need for enhanced protection strategies (e.g., adjuvanted/high-dose vaccines, monoclonal antibodies, or antivirals) for immunocompromised and elderly populations.

Limitations:

• Statistical Power: Some estimates for rare outcomes (e.g., death) and specific subgroups (immunocompromised, specific subclades) had wide confidence intervals, leading to non-significant results in some strata.
• Residual Confounding: Despite adjustment, unmeasured factors (e.g., frailty, health-seeking behavior) could influence both vaccination status and disease severity.
• Sample Size: Limited ability to perform deep sub-analyses on specific comorbidity thresholds or rare subtype-severity combinations.
• Preprint Status: As a preprint, the data has not yet undergone peer review.

Conclusion:
The 2024–2025 influenza vaccine provided moderate protection against hospitalization and substantial protection against severe in-hospital outcomes and death in U.S. adults. While effectiveness was slightly reduced against A(H3N2) and in older/immunocompromised populations, the vaccine remained a critical tool for mitigating the severity of the influenza season.