Recombinant Lactococcus lactis Pili for HIV Mucosal Immunity
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current HIV vaccines have been ineffective in preventing infection and modifying disease progression, particularly in protecting the gastrointestinal tract, which is a major site of CD4+ T cell depletion and viral replication.
Innovation Solution
A recombinant Lactococcus lactis expressing a fusion construct of HIV Gag p24 and Cpa protein on its type-3 pilus is administered orally, followed by an intramuscular boost with MVA expressing Gag p24, to elicit mucosal and systemic immune responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional HIV vaccines (AIDSVAX B/B, AIDSVAX B/E, MRKAD5) are administered, then antibody responses or CD8+ T cell responses are elicited, but protection against HIV infection and disease progression is not achieved
Solution Approach 1:
The vaccine system is segmented into two distinct components: an oral prime phase using recombinant L. lactis expressing HIV antigens on surface proteins, and a parenteral boost phase using conventional vaccine formulations. This segmentation allows each component to target specific immune compartments (mucosal vs. systemic), resolving the contradiction by improving overall effectiveness without requiring a single complex vaccine formulation
Solution Approach 2:
The recombinant L. lactis serves as an intermediary delivery system that presents HIV antigens on its surface proteins (such as PrgH, PrgI, or PilV) to mucosal immune tissues. This intermediary approach enables effective antigen delivery to gut-associated lymphoid tissue, which conventional vaccines fail to access, thereby improving vaccine effectiveness without increasing the complexity of the antigen itself
2Reliability
If vaccines target systemic immunity, then antibody responses are generated, but protection at the gastrointestinal tract (major site of CD4+ T cell depletion and viral replication) is insufficient
Solution Approach 1:
The oral prime phase using recombinant L. lactis performs preliminary action by establishing mucosal immunity at the gastrointestinal tract before potential HIV exposure. This preliminary establishment of IgA antibodies and mucosal T cell responses at the target site (gut-associated lymphoid tissue) ensures protection is in place before the virus can establish infection, resolving the contradiction between achieving mucosal protection and maintaining simple administration
Solution Approach 2:
The recombinant L. lactis utilizes its natural properties as a probiotic bacterium that survives gastric acid and colonizes the gastrointestinal tract. This self-service capability allows the vaccine vehicle to automatically deliver antigens to the target mucosal site without requiring complex delivery mechanisms, thereby improving mucosal protection while maintaining ease of administration
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach induces strong mucosal and systemic antibody responses, as well as CD8+ T cell responses, particularly at the gastrointestinal mucosa, enhancing protection against HIV infection and potentially slowing disease progression.
Implementation Method 1
expressing a type-3 pilus found in Streptococcus pyogenes and a fusion construct of Gag p24 and Cpa protein at the tip of the pilus
Implementation Method 2
eliciting HIV-specific immune responses in the mucosal and systemic compartments of a subject
Implementation Method 3
eliciting HIV-specific immune responses in the mucosal and systemic compartments of a subject
Implementation Method 4
induces strong mucosal and systemic antibody responses, as well as CD8+ T cell responses
Data Source
Figure 1
Figure 2
Figure 3~4B
AI summary
This disclosure relates to recombinant bacteria, e.g. L. lactis, expressing heterologous pili containing human immunodeficiency virus (HIV) antigens. In certain embodiments, the recombinant bacteria are administered in combination with other HIV antigens, nucleic acids encoding HIV antigens, recombinant virus encoding HIV antigens, anti-viral agents and/or adjuvants in an effective amount to elicit a mucosal immune response against HIV.