Supplement request to DAIDS to Manufacture an mRNA/LNP encoding an HIV envelope designed to bind and stimulate multiple V2 Apex broadly neutralizing antibody B cell lineages Barton Haynes, CHAVD PI Thomas Denny, Investigator, manufacture team This request is to produce GMP an mRNA immunogen that encodes an Env that binds to multiple V2 apex broadly neutralizing antibody (bnAb) naïve B cell precursors that are required for the acquisition of bnAb breadth against the V2 apex of HIV-1. This mRNA encodes a gp150 immunogen (OPT4.R189T “shielded”) targeting 6 V2 apex UCAs and will be tested both as a prime and as an immunofocusing boost for induction of V2 apex bnAbs. The immunogen that this mRNA will be compared with as a prime is a similar protein, OPT4 “unshielded” Env-ferritin nanoparticle (NP), that targets 9 V2 apex UCAs. Moreover, since the mRNA OPT4.R189T “shielded” Env can boost on-track V2 apex bnAbs in monkeys, it will be tested as a boosting immunogen with the protein prime, OPT4 “unshielded” Env-ferritin nanoparticle (NP), that is also requested to be manufactured in a separate CHAVD manufacturing supplement request. What follows below is the rationale for requesting the production of the OPT4.R189T “shielded” Env gp150 mRNA/LNP under GMP conditions in this Y6 CHAVD supplement. Specific Aim 1. Demonstration batch production and analytical development of candidate mRNAs. Specific Aim 2. Deliver final drug substances and drug products for toxicology studies and clinical testing Specific Aim 3. Develop and deliver a regulatory strategy to enable Phase I proof of concept clinical studies.