Abstract
Conventional vaccinations and immunotherapies have encountered major roadblocks in preventing infectious diseases like HIV, influenza, and malaria. These challenges are due to the high genomic variation and immunomodulatory mechanisms inherent to these diseases. Passive transfer of broadly neutralizing antibodies may offer partial protection, but these treatments require repeated dosing. Some recombinant viral vectors, such as those based on lentiviruses and adeno-associated viruses (AAVs), can confer long-term transgene expression in the host after a single dose. Particularly, recombinant (r)AAVs have emerged as favorable vectors, given their high in vivo transduction efficiency, proven clinical efficacy, and low immunogenicity profiles. Hence, rAAVs are being explored to deliver recombinant antibodies to confer immunity against infections or to diminish the severity of disease. When used as a vaccination vector for the delivery of antigens, rAAVs enable de novo synthesis of foreign proteins with the conformation and topology that resemble those of natural pathogens. However, technical hurdles like pre-existing immunity to the rAAV capsid and production of anti-drug antibodies can reduce the efficacy of rAAV-vectored immunotherapies. This review summarizes rAAV-based prophylactic and therapeutic strategies developed against infectious diseases that are currently being tested in pre-clinical and clinical studies. Technical challenges and potential solutions will also be discussed.
Highlights
Infectious diseases are among the biggest threats to our society
One of the biggest concerns with the recent COVID-19 pandemic, which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the possibility of vaccine-mediated antibody-dependent enhancement (ADE) effect, since similar outcomes have been observed with other coronavirus infections [12]
Pfizer/BioNTech and Moderna have each developed a vectored strategy, in which mRNA encoding the coronavirus spike (S) protein packaged in lipid nanoparticles (LNPs) is delivered to the body to mediate de novo synthesis of the S protein, so that the conformation and topology of the antigen best resembles the native protein that is decorated on SARS-CoV-2 [13, 14]
Summary
Infectious diseases are among the biggest threats to our society. They range from ancient maladies, such as malaria and influenza, to modern illnesses, such as human immunodeficiency virus (HIV)-1 and the coronavirus disease of 2019 (COVID-19) pandemic. Other challenges, such as anti-drug antibodies (ADAs), mAb-mediated toxicity, and issues related to long-term antigen expression in non-target tissues, are unique challenges for rAAV-based immunotherapy platforms. If these findings hold true in clinical settings, one possibility of reducing ADAs is to use B cell-targeting rAAV vectors, such as those based on AAV6, for preferential mAb expression via gene-edited B cells [126, 127].
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