TL;DR: 

AAV vectors, best known in gene therapy, could be repurposed into safe, customizable, one-shot vaccines with long-lasting protection; however, significant challenges remain, including size limitations, pre-existing immunity, and manufacturing. This post is part of my involvement in biosecurity through the list of short-term projects

Introduction

Vaccines are among the greatest achievements in public health, having eradicated smallpox and drastically reduced the burden of diseases such as polio and measles. Yet, global health continues to face persistent challenges including HIV, malaria, tuberculosis, and zoonotic threats. The COVID-19 pandemic highlighted how quickly emerging pathogens can destabilize societies, intensifying the need for innovative vaccine platforms.

Beyond traditional live-attenuated or protein-based vaccines, novel technologies such as mRNA, viral vectors, and synthetic biology-designed systems are paving the way for next-generation vaccines. Viral vectors, genetically engineered from viruses to deliver foreign genes, have proven powerful in eliciting strong T-cell and B-cell immune responses. For example, adenovirus-based vaccines such as ChAdOx1 nCoV-19 (Oxford/AstraZeneca) and Ad26.COV-2.S (Johnson & Johnson) were rapidly developed during COVID-19.

Adeno-associated virus (AAV) vectors, widely used in gene therapy, are gaining attention as promising platforms for vaccines. Their safety, ability to induce long-lasting immunity, and versatility in design make them compelling candidates—despite technical challenges such as manufacturing complexity and pre-existing immunity. For broader context, see Tang et al.’s review on Past, Present, and Future of Viral Vector Vaccines.

The Basics 

AAV is a tiny virus (25 nm) from the Parvoviridae family, discovered in the 1960s as a contaminant in adenovirus samples. Classified in the Dependoparvovirus genus, it cannot replicate without a “helper virus” such as adenovirus or herpes simplex virus. Importantly, AAV is non-pathogenic, making it intrinsically safer than many viral counterparts.

Its genome is a short single-stranded DNA (4.7 kb), limiting its genetic cargo but providing stability. Initially used for gene therapy, AAV gained recognition for its ability to express therapeutic genes with minimal immune response compared to adenoviruses. This property made scientists reconsider its potential in vaccinology, where both active vaccination and passive immunotherapy could be explored.

• Active Vaccination: AAV delivers genetic instructions to cells, producing a viral antigen that trains the immune system.

• Passive Immunotherapy: AAV directly encodes protective antibodies, turning the body into a factory for therapeutic biologics.

Thus, AAV offers a dual role—either educating the immune system or supplementing it with ready-made defenses.

Why AAV Might Be a Better Vaccine Tool

• Safety first – Derived from a virus that causes no disease. Replication-deficient vectors cannot spread.

• Lasting effect – A single dose can induce immune protection lasting months or years.

• Customizable design – Capsid modifications allow scientists to fine-tune immune responses or evade pre-existing immunity.

Promising Examples in Preclinical Studies

1. Henipaviruses (Nipah & Hendra): In mice and hamsters, a single AAV-based vaccine provided complete protection against Nipah and partial protection against Hendra (Frontiers).

2. HIV/SIV: Non-human primates immunized with AAV developed both antibody and T-cell responses, with some animals fully protected (EuropePMC).

3. SARS-CoV-2 (COVID-19): Studies in mice show intranasal or intramuscular delivery of AAV encoding spike protein can induce durable antibody and cellular immunity, supporting its role in respiratory pathogens (Frontiers in Immunology).

Strengths and Challenges of AAV Vaccines

Challenges:

• Cargo size limit – AAV’s 4.7 kb genome restricts large antigen use.

• Pre-existing immunity – Many humans have neutralizing antibodies to natural AAV strains.

• Manufacturing cost – Large-scale AAV production remains expensive and complex.

The Road Ahead

Future research must focus on:

• Engineering novel AAV capsids to avoid immune recognition.

• Developing larger-capacity variants or split-genome strategies.

• Scaling up manufacturing for equitable access.

If successful, AAV vaccines could reshape pandemic preparedness, offering single-dose, durable, customizable vaccines for both global health and low-resource settings.

Final Thoughts

Nieto & Salvetti (2014) reframed AAV from a gene therapy tool into a transformative vaccine platform. By bridging safety, durability, and adaptability, AAV vectors may complement or even surpass existing viral platforms. Their dual-use potential—active vaccines or antibody gene-delivery—could revolutionize how we respond to emerging infectious diseases.

📖 Read the full article here: Frontiers in Immunology