Flu Vaccine Clinical Trials — Pre-Licensure Safety

Was the flu shot tested with a placebo before it was approved? This page documents the pre-licensure clinical trial safety data for every influenza vaccine licensed in the United States.

Clinical trial data for the influenza vaccines licensed for use in US children. The earliest brands (Fluzone IIV3, 1980; Fluvirin IIV3, 1988) were licensed with no control at all. Subsequent brands were licensed against prior flu vaccines or mixed comparators that included other licensed vaccines and unlicensed substances. Annual reformulations receive no clinical trial of their own — each year's flu shot is assumed safe based on the original brand-specific trial conducted with different antigens decades earlier.

Brand Licensure Table

YearBrandCompanyControl
1980Fluzone IIV3SanofiNo control
1988Fluvirin IIV3SeqirusNo control
2005Fluarix IIV3GSKFluzone IIV3
2006Flulaval IIV3GSKFluzone IIV3
2007Afluria IIV3SeqirusFluzone IIV3
2012Flucelvax IIV3SeqirusFluvirin IIV3
2012Fluarix IIV4GSKPCV13, Havrix, Varivax, or unlicensed vaccine
2013Fluzone IIV4SanofiFluzone IIV3 or unlicensed vaccines
2013Flulaval IIV4GSKFluzone IIV4, Fluarix IIV3, or Havrix
2016Afluria IIV4SeqirusFluzone IIV4 or Fluarix IIV4
2016Flucelvax IIV4SeqirusAfluria IIV4, Menveo, or Menveo+Saline

IIV = Inactivated Influenza Vaccine; 3 = trivalent; 4 = quadrivalent

The Foundational No-Control Brands

Fluzone IIV3 (Sanofi, 1980)

The oldest brand on the list and the foundation of the entire flu vaccine pyramid. Licensed in 1980 with no control group. Most subsequent brands (Fluarix, Flulaval, Afluria, Fluzone IIV4) were licensed against Fluzone IIV3.

Fluvirin IIV3 (Seqirus, 1988)

The second-oldest brand. Licensed in 1988 with no control group. Used as the control for Flucelvax IIV3 in 2012.

Mixed Comparator Problem

Several recent brands used mixed comparators — different participants in the same trial received different control products:

These are not single consistent control groups; they are collections of different active substances. Statistical analysis comparing the vaccinated group to a heterogeneous control group does not isolate vaccine-specific effects.

The No-Clinical-Trial Annual Reformulation Problem

The influenza vaccine is the only vaccine on the childhood schedule that is substantively reformulated every year. Each annual version targets different strains, selected by WHO surveillance in February for the following Northern Hemisphere flu season.

No new clinical trial is conducted for each annual reformulation. The FDA accepts each year's formulation as safe based on the original licensure trial for that brand. The brand's original trial may have been conducted with:

1. A completely different set of influenza antigens decades earlier

2. Using a prior flu vaccine (or no control) as the comparator

3. With a safety monitoring window of a few days to weeks

The safety of the 2025 flu shot administered to a 6-month-old infant therefore rests on, e.g., a 1980 Fluzone IIV3 trial of unspecified design with no control group.

Pyramid Tracing

The entire flu vaccine safety chain ultimately traces to two no-control trials in the 1980s:

```

Fluzone IIV3 (1980) — no control

↓

Fluarix IIV3 (2005), Flulaval IIV3 (2006), Afluria IIV3 (2007), Fluzone IIV4 (2013)

↓

Fluarix IIV4 (2012), Flulaval IIV4 (2013), Afluria IIV4 (2016)

Fluvirin IIV3 (1988) — no control

↓

Flucelvax IIV3 (2012)

↓

Flucelvax IIV4 (2016)

```

Schedule

DoseTiming
Dose 16 months
Dose 2 (first year only)7 months
Annual boosterEvery subsequent fall/winter

For children under 9 receiving flu vaccine for the first time, two doses are required. After the first year, an annual booster is recommended every fall/winter for all Americans 6 months and older.

Disease Context

Influenza causes seasonal respiratory illness with substantial annual mortality variation. Severe outcomes are concentrated in the elderly, immunocompromised, and very young. Strain composition varies year-to-year, which is the rationale for annual reformulation. Vaccine efficacy varies by year depending on the match between the formulated strains and circulating strains.

See Also

Influenza Vaccines (Post-Licensure), Pre-Licensure Safety Testing, Childhood Vaccine Schedule, Herd Immunity, VAERS, GSK, Sanofi

Frequently Asked Questions

Frequently Asked Questions

Was the flu shot tested with a placebo before approval?
No. The foundational flu vaccines — Fluzone IIV3 (Sanofi, 1980) and Fluvirin IIV3 (Seqirus, 1988) — were licensed with no control group at all. Every subsequent flu vaccine brand was tested against one of these earlier flu vaccines or a mix of other licensed vaccines. No flu vaccine on the US schedule was ever tested against an inert saline placebo. This is documented in each product's FDA-approved package insert.
Does the flu shot get a new clinical trial every year when the strains change?
No. Annual reformulations receive no new clinical trial. Each year's flu shot contains different antigens targeting new predicted strains, but the FDA accepts it as safe based on the original brand-specific trial — which may have been conducted decades earlier with completely different antigens and no control group. The safety of a 2025 flu shot given to an infant therefore rests on, for example, the 1980 Fluzone IIV3 trial of unspecified design.
What was the control group for FluLaval and Fluarix clinical trials?
FluLaval IIV3 (2006) and Fluarix IIV3 (2005) were both tested against Fluzone IIV3, which was licensed in 1980 with no control group. The quadrivalent versions used mixed comparators — for example, Fluarix IIV4's trial control consisted of PCV13, Havrix, Varivax, or an unlicensed vaccine, depending on which participant you were. These mixed comparator designs make it impossible to isolate vaccine-specific adverse effects.
How many flu vaccine brands are on the US schedule and how are they connected?
There are 11 licensed influenza vaccine products across 6 brands (Fluzone, Fluvirin, Fluarix, FluLaval, Afluria, Flucelvax), spanning trivalent and quadrivalent versions. The entire safety chain traces back to two no-control trials from the 1980s — Fluzone IIV3 (1980) and Fluvirin IIV3 (1988). Every subsequent brand was tested against one of these or against another brand that was itself tested against one of these. This pyramid structure is documented in the FDA package inserts.
Why is the flu vaccine given to 6-month-old babies?
The CDC recommends annual flu vaccination starting at 6 months of age. Children under 9 receiving the vaccine for the first time require two doses. The rationale is protection against seasonal influenza, which can cause severe outcomes in very young children. However, the original clinical trials that licensed these products were conducted decades ago with different strains, no placebo controls, and monitoring windows of days to weeks.

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