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First-in-Human HIV Vaccine Induces Virus-Specific Neutralizing Antibodies

• Researchers have developed a novel HIV vaccine formulation combining a new adjuvant (3M-052-AF) with an HIV Env protein complex. • The vaccine successfully induced neutralizing antibodies in humans against an HIV strain matching the vaccine's envelope. • The 3M-052-AF adjuvant, signaling via TLR7/TLR8, proved safe and effective in boosting target-specific neutralizing antibody production. • Further optimization is needed to broaden the neutralizing antibody response for protection against diverse circulating HIV strains.

Researchers at Fred Hutchinson Cancer Center, led by Dr. Julie McElrath, have achieved a significant milestone in HIV vaccine development. Their study, published in the Journal of Experimental Medicine, reports the first-ever induction of virus-specific neutralizing antibodies in humans using a novel HIV vaccine formulation. This formulation combines a new class of vaccine adjuvants (3M-052-AF) with a recombinant HIV Env protein immunogen (Env trimers). The trial represents a crucial step forward, demonstrating the potential to train the immune system to produce antibodies that could prevent HIV infection.
The new vaccine formulation contains two key ingredients: the Env trimer, engineered to mimic the native structure of the HIV Env on the surface of the HIV virion, and the adjuvant 3M-052-AF. According to Dr. William Hahn, Clinical Assistant Professor at the University of Washington, this is the first description of using 3M-052-AF in healthy volunteers in clinical trials. Unlike previous HIV vaccine formulations that often use a single HIV Env protein, the Env trimer presents a more native-like target for antibody development.

Overcoming Limitations of Previous Approaches

Previous studies using the aluminum hydroxide (alum) adjuvant with Env trimers showed antibody binding to the base of the trimer, a site normally hidden and less effective for neutralization. The McElrath group aimed to shift the antibody response towards the trimer apex, enhancing neutralizing activity. Vaccine studies in monkeys indicated that the synthetic imidazoquinolinone 3M-052 could effectively boost the production of target-specific, neutralizing antibodies.

Clinical Trial Results and Implications

The first-in-human trial demonstrated that the 3M-052-AF adjuvant, signaling via toll-like receptor 7 and 8 (TLR7/TLR8), was safe and effective. "The adjuvant was safe and the 5 microgram dose of 3M-052-AF/Alum induced antibodies capable of neutralizing a wild-type HIV matched to the vaccine," commented Dr. Hahn. Intriguingly, the dual adjuvant vaccine shifted the antibody target site on the Env trimer from the base to the apex.

Future Directions

Despite the promising results, Dr. Hahn noted a limitation: "Unfortunately, the types of neutralizing antibodies the vaccine induced were relatively narrowly matched to the vaccine and ultimately the vaccine will need to neutralize additional circulating HIV strains that cause clinical infection." Therefore, continued optimization is necessary to elicit broadly neutralizing antibodies for protection against the diverse range of circulating HIV strains. This study marks a significant advancement in HIV vaccine platform development, paving the way for future research focused on broadening the neutralizing antibody response.
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Reference News

[1]
First in-human HIV vaccine to induce virus-specific neutralizing antibodies
fredhutch.org · Oct 17, 2024

Fred Hutchinson Cancer Center researchers, led by Dr. Julie McElrath, developed a new HIV vaccine formulation combining ...

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