AAV Aggregation vs. Adenovirus Aggregation: Which Causes Greater Loss of Infectivity?

In general, adenovirus aggregation usually causes a much greater loss of infectivity than AAV aggregation.

Here is the practical difference:

Feature	AAV Aggregation	Adenovirus Aggregation
Capsid size	~25 nm	~90–100 nm
Particle stability	Very stable	Less stable at high concentration
Aggregation tendency	Moderate	Higher
Sensitivity to vortex/shear	Relatively resistant	More sensitive
Impact on infectivity	Often partial reduction	Can be severe
Risk during concentration	Moderate	High
Reversibility	Sometimes partially reversible	Often irreversible

Why Adenovirus Loses Infectivity More Easily

Adenovirus is:

• Much larger
• More structurally complex
• More prone to particle-particle interaction
• More sensitive to formulation conditions

When adenovirus aggregates:

• receptor binding becomes impaired
• internalization efficiency drops
• plaque-forming activity decreases rapidly
• large aggregates may precipitate irreversibly

As a result, even if total VP remains high, the functional titer (PFU or IU) can collapse significantly.

This is why adenovirus preparations often show:

• high VP count
• but low PFU/VP ratio after aggregation

AAV Aggregation Is Often Less Damaging

AAV capsids are:

• smaller
• mechanically tougher
• naturally highly stable

Mild AAV aggregation may:

• reduce transduction efficiency somewhat
• alter biodistribution
• increase immune recognition

But many aggregated AAV particles can still remain partially functional.

Loss of infectivity is usually less catastrophic compared with adenovirus.

Important Exception

Severe AAV aggregation can still become problematic, especially:

• at ultra-high titers (>10¹⁴ VG/mL)
• after repeated freeze-thaw cycles
• in low-salt buffers
• with hydrophobic transgenes/capsids

Large AAV aggregates can:

• trigger immune responses
• clog filters
• reduce in vivo transduction consistency

Bottom Line

Under most production and storage conditions:

Adenovirus aggregation generally causes much greater infectivity loss than AAV aggregation.

This is one reason adenovirus formulation buffers and handling procedures are usually more stringent and sensitive than those used for AAV.