A Clinical Trial to Evaluate the Safety and Immunogenicity of CH505M5 N197D mRNA-gp160 Followed by CH505 TF mRNA-gp160 in Adults in Overall Good Health Without HIV

1. Volunteer who is breastfeeding/chestfeeding or pregnant.

2. Body mass index (BMI) ≥ 40. Enrollment of individuals with BMI ≥ 40, whom the site investigator assesses are in good health, may be considered by PSRT approval.

3. Diabetes mellitus (DM). Type 2 DM controlled with diet alone (and confirmed by HgbA1c ≤ 8% within the last 6 months) or a history of isolated gestational diabetes are not exclusionary. Enrollment of individuals with Type 2 DM that is well controlled on hypoglycemic agent(s) may be considered by the PSRT on a case-by-case basis, provided that the HgbA1c is ≤ 8% within the last 6 months (sites may draw these at screening).

4. Previous or current recipient of an investigational HIV vaccine or HIV mAb (previous placebo/control recipients are not excluded).

5. Receipt of non-HIV investigational vaccine(s) received within the last 1 year. Exceptions include vaccines that have subsequently undergone licensure or Emergency Use Authorization (EUA) by the FDA or World Health Organization (WHO) Emergency Use Listing (EUL), or if outside the US, by the national Regulatory Authority (RA) authorizing this clinical trial.

6. Congenital or acquired immunodeficiency, including systemic medication use likely to impair immune response to vaccine in the opinion of the site investigator, such as glucocorticoid use, ≥ prednisone 10 mg/day within 3 months prior to enrollment.

7. Blood products or immunoglobulin within 16 weeks prior to enrollment; receipt of immunoglobulin within 16 weeks prior to enrollment requires PSRT approval.

8. Receipt of any of the following within 4 weeks prior to enrollment:

* Live replicating vaccine

* Any mRNA-based vaccine with FDA licensure, FDA EUA, or WHO EUL

* ACAM2000 vaccine \> 28 days prior with a vaccination scab still present.

9. Receipt of any vaccine that is not covered in exclusion criterion #8 within 14 days prior to enrollment. Please note this includes replication-incompetent vaccines such as the Jynneos vaccine for the prevention of mpox disease.

10. History of myocarditis and/or pericarditis.

11. Initiation of Ag-based immunotherapy for allergies within the previous year (stable immunotherapy is not exclusionary); inclusion of participants who initiated immunotherapy within the previous year requires PSRT approval.

12. Receipt of investigational research agents with a half-life of 7 or fewer days within 4 weeks prior to enrollment. If a potential participant has received investigational agents with a half-life of more than 7 days (or unknown half-life) within the past year, PSRT approval is required for enrollment.

13. History of serious reaction (eg, hypersensitivity, anaphylaxis) to any mRNA vaccine, including Comirnaty® (Pfizer) and Spikevax® (Moderna), or to any drug administered systemically as a polyethylene glycol containing LNP, including doxorubicin (Doxil, Caelyx, ThermoDox), cisplatin (Lipoplatin) and irinotecan (Onivyde).

14. Hereditary angioedema, acquired angioedema, or idiopathic forms of angioedema.

15. Urticaria within the last year unless it was caused by a known, definable, and avoidable trigger (ie, urticaria by a known, definable and avoidable trigger would not be exclusionary).

16. History of chronic urticaria or urticaria previously associated with immunization.

17. Bleeding disorder diagnosed by a clinician that would make study procedures a contraindication.

18. History of seizure(s) within the past 3 years. Also exclude if volunteer has used medications in order to prevent or treat seizure(s) at any time within the past 3 years.

19. Asplenia or functional asplenia.

20. Active duty and reserve US military personnel.

21. Any other chronic or clinically significant condition that, in the clinical judgment of the investigator, would jeopardize the safety or rights of the study participant, hinder their ability to participate in the study, or affect their immune responses to study products. Such conditions include but not limited to: clinically significant forms of substance use or alcohol use disorder(s), serious psychiatric disorders, any suicide attempt within the past 1 year (if between 1 and 2 years, consult PSRT for approval), or cancer that, in the clinical judgement of the site investigator, has potential for recurrence (excluding basal cell carcinoma).

22. Asthma is excluded if the participant has ANY of the following:

* Required either oral or parenteral corticosteroids for an exacerbation 2 or more times within the past year; OR

* Needed emergency care, urgent care, hospitalization, or intubation for an acute asthma exacerbation within the past year (eg, would NOT exclude individuals with asthma who meet all other criteria but sought urgent/emergent care solely for asthma medication refills or coexisting conditions unrelated to asthma); OR

* Uses a short-acting rescue inhaler more than 2 days per week for acute asthma symptoms (ie, not for preventive treatment prior to athletic activity); OR

* Uses medium- to high-dose inhaled corticosteroids (\> 250 mcg fluticasone or therapeutic equivalent per day), whether in single-therapy or dual-therapy inhalers (ie, with a long-acting beta agonist \[LABA\]); OR

* Uses more than 1 medication for maintenance therapy daily. Inclusion of anyone on a stable dose of more than 1 medication for maintenance therapy daily for greater than 2 years requires PSRT approval.

23. A participant with a history of a potential immune-mediated medical condition (PIMMC), either active or remote. Not exclusionary: 1) Remote history of Bell's palsy (\> 2 years ago) not associated with other neurologic symptoms and 2) mild psoriasis or other mild, uncomplicated, localized or dermatologic condition that does not require ongoing systemic treatment.

24. History of allergy to local anesthetic (Novocain, Lidocaine).

25. Investigator concern for difficulty with venous access based on clinical history and physical examination. For example, persons with a history of IV drug use or substantial difficulty with previous blood draws.

What this study is about