This is a single-center, observer-blinded, dosage-escalation trial to evaluate the safety, tolerability, reactogenicity, and immunogenicity of ChAd155-RG compared with RABAVERT in rabies virus-naïve healthy male and non-pregnant female adult subjects ages 18-49. There are 4 dose groups: Group A will receive ChAd155-RG at the lower dosage (5x1010vp) on Day 1, then placebo injections on Days 8, 15, and 22; Group B will receive ChAd155-RG at the higher dosage (1x1011vp) on Day 1, then placebo injections on Days 8, 15, and 22; Group C will receive ChAd155-RG at the higher dosage (1x1011vp) on Days 1 and 15, and placebo injections on Days 8 and 22; Group D will receive RABAVERT at the standard dose (1 mL) on Days 1, 8, and 22, and a placebo injection on Day 15. Since this is a dosage-escalation study, sentinel subjects will be used at each dosage level before non-sentinel subjects will be enrolled. The study will be conducted at Emory University Vaccine and Treatment Evaluation Unit (VTEU). This trial is expected to take approximately 48 months to complete. The duration of each subject's participation is approximately 13 months, from recruitment through the last study visit. The primary objectives of this study are: 1) Assessment of the safety, tolerability, and reactogenicity of one dose of ChAd155-RG at 5x1010vp per dose, or one or two doses of ChAd155-RG at 1x1011vp per dose; 2) Comparison of the safety, tolerability, and reactogenicity of one or two doses of ChAd155-RG, with three doses of RABAVERT.

This is a single-center, observer-blinded, Phase 1, dosage-escalation trial to evaluate the safety, tolerability, reactogenicity, and immunogenicity of ChAd155-RG compared with RABAVERT in rabies virus-naïve healthy male and non-pregnant female adult subjects ages 18-49. Subjects who have never received a licensed or investigational rabies virus vaccine, or an Ad-based investigational vaccine, and who have never been exposed to a rabid animal will be eligible for enrollment. There are 4 dose groups: Group A will receive ChAd155-RG at the lower dosage (5x1010vp) on Day 1, then placebo injections on Days 8, 15, and 22; Group B will receive ChAd155-RG at the higher dosage (1x1011vp) on Day 1, then placebo injections on Days 8, 15, and 22; Group C will receive ChAd155-RG at the higher dosage (1x1011vp) on Days 1 and 15, and placebo injections on Days 8 and 22; Group D will receive RABAVERT at the standard dose (1 mL) on Days 1, 8, and 22, and a placebo injection on Day 15. Since this is a dosage-escalation study, sentinel subjects will be used at each dosage level before non-sentinel subjects will be enrolled. The SMC will review the available safety, reactogenicity, AE, and lab data of all the sentinel subjects, and will decide if the remaining non-sentinel subjects should be enrolled. The study will be conducted at Emory University Vaccine and Treatment Evaluation Unit (VTEU). This trial is expected to take approximately 48 months to complete. The duration of each subject's participation is approximately 13 months, from recruitment through the last study visit. The primary objectives of this study are: 1) Assessment of the safety, tolerability, and reactogenicity of one dose of ChAd155-RG at 5x1010vp per dose, or one or two doses of ChAd155-RG at 1x1011vp per dose; 2) Comparison of the safety, tolerability, and reactogenicity of one or two doses of ChAd155-RG, with three doses of RABAVERT. The secondary objective is to assess the serum rabies VNA levels by a standard, WHO-approved, RFFIT, as assessed by immune response kinetics (through approximately 12 months after first dose of vaccine), seroconversion rates, and peak GMT in each treatment arm.

Inclusion Criteria:

1. Must be a male or female aged 18-49 years old (inclusive) at the time of first vaccination.

2. Must be able to provide written informed consent.

3. Must have a body mass index (BMI) = / >18.5 and <35.0 kg/m^2

4. Must be in good health based on physical examination, vital signs*, medical history, safety labs**, and the investigator's clinical judgment.

   *Vital signs must be within the normal ranges. If a subject has elevated systolic or diastolic blood pressure, subject may rest for 10 minutes in a quiet room and the blood pressure may be retaken.

   **Safety lab normal ranges will be those used by the reference clinical lab. Protocol-specific criteria for individual subjects are listed in criteria #5.

5. Must have acceptable* lab values within 28 days before enrollment. *Acceptable values include:

   • Hemoglobin: women >11.6 g/dL, men >13.1 g/dL
   • White blood cells: >3,700 but <10,900 cells/mm^3
   • Absolute neutrophil count: = / >1,500 cells/mm^3
   • Absolute lymphocyte count: = / >850 cells/mm^3
   • Platelets: >139,000 but <401,000 per mm^3
   • Urine dipstick (clean urine sample): protein <1+, glucose negative
   • Alanine transaminase and aspartate transaminase (ALT, AST) <1.1 x institutional upper limit of normal (ULN)
   • Total bilirubin <1.1x institutional ULN
   • Blood urea nitrogen (BUN) <1 x institutional ULN
   • Serum creatinine <1x institutional ULN
   • If lab screening tests are out of range, repeating them is permitted once, provided there is an alternative explanation for the out-of-range value.

6. Women of childbearing potential* must have a negative serum pregnancy test at screening and negative urine pregnancy tests within 24 hours before each vaccination.

   • Women of non-childbearing potential, defined as postmenopausal (any age with amenorrhea for = / >12 months without other known or suspected cause for amenorrhea), or surgically sterile [hysterectomy, bilateral tubal ligation, bilateral oophorectomy, or successful Essure(R) placement (permanent, non-surgical, non-hormonal sterilization)] with documented confirmation test = / >3 months after the procedure), are not required to use contraceptive methods.

7. Women of childbearing potential must use an acceptable method of contraception* from 28 days before the first vaccination until = / >60 days after the last vaccination.

   *Acceptable methods of contraception include: prescription oral contraceptives, contraceptive injections, intrauterine device (IUD), implants, vaginal ring, double-barrier method, contraceptive patch, male partner who had a vasectomy at least 6 months prior to study enrollment, abstinence (defined as refraining from heterosexual intercourse during participation in this trial [from 28 days before the first vaccination until = / >60 days after the last vaccination]).

8. Female subjects must agree to not donate eggs (ova, oocytes) from the start of screening until = / >60 days after the last vaccination.

9. Male subjects who have not had a vasectomy* and are sexually active with a woman of childbearing potential must agree to use an acceptable method of contraception**.

   *Men who have had a vasectomy must have had the procedure performed at least 6 months prior to study enrollment.

   **Acceptable methods of contraception must be used from the first vaccination until = / >60 days after the last vaccination, and include: abstinence (defined as refraining from heterosexual intercourse with a female partner of childbearing potential during participation in this trial [from 28 days before the first vaccination until = / >60 days after the last vaccination]; a double-barrier method, such as condom with spermicidal foam/gel/film/cream/suppository and partner with occlusive cap (diaphragm, cervical/vault caps); if the female partner is using an acceptable method of contraception (see Inclusion Criterion #7), a single-barrier method for the male subject is acceptable.

10. Male subjects must agree to not donate sperm from the start of screening until = / >60 days after the last vaccination.

11. Must be available and willing to participate for the duration of this trial.

12. Must have a means to be contacted by telephone.

Exclusion Criteria:

1. Was ever vaccinated with a licensed or investigational rabies vaccine* or was diagnosed with rabies exposure, infection, or disease.

   *Includes RABAVERT and Imovax. Subject's verbal history will suffice.

2. Has a higher risk than the average US resident with regard to exposure to rabies, per the Rabavert package insert and rabies vaccination recommendations from the CDC*.

   • People at high risk of exposure to rabies, such as veterinarians, animal handlers, rabies laboratory workers, spelunkers, and rabies biologics production workers.
   • People whose activities bring them into frequent contact with rabies virus or with possibly rabid animals.
   • International travelers who are likely to come in contact with animals in parts of the world where rabies is common.

3. Was ever vaccinated with a licensed or investigational Ad vector or Ad vaccine.

4. Is currently taking chloroquine or hydroxychloroquine.

5. Was diagnosed with laboratory-confirmed COVID-19 (PCR or antigen-based test) in the preceding 28 days.

6. Positive serology for HIV antibody, HCV antibody, or Hepatitis B surface antigen (HBsAg).

7. Has known allergy or history of anaphylaxis or other serious adverse reaction to a vaccine or vaccine products*.

   *Including egg products, aminoglycosides, gelatin, sorbitol, tris (hydroxymethyl)-amino methane (THAM), or any of the constituents of the study vaccines.

8. Has severe allergy or anaphylaxis to latex.

9. Has an acute illness or temperature = / >38.0 Degrees Celsius on Day 1*.

   *Subjects with fever or acute illness on the day of vaccination may be re-assessed and enrolled if healthy or only minor residual symptoms remain within 3 days.

10. Female subjects who are pregnant or breastfeeding, or planning to become pregnant while enrolled in this trial and at least 60 days after last vaccination.

11. Has history of autoimmune disease, or clinically significant cardiac, pulmonary, hepatic, rheumatologic, or renal disease by history, physical examination, and/or lab studies.

12. Has history of malignancy other than squamous cell or basal cell skin cancer, unless there has been surgical excision that is considered to have achieved cure*.

    *Subjects with a history of skin cancer must not be vaccinated at the previous tumor site.

13. Has known or suspected congenital or acquired immunodeficiency, or recent history or current use of immunosuppressive therapy*.

    *Anti-cancer chemotherapy or radiation therapy within the preceding 6 months, or long-term (= / >2 weeks within the previous 3 months) systemic corticosteroid therapy (at a dosage of = / >0.5 mg/kg/day). Intranasal or topical prednisone (or equivalent) are allowed.

14. Is post-organ and/or stem cell transplant, whether or not on chronic immunosuppressive therapy.

15. Had major surgery (per the investigator's judgment) within 4 weeks before study entry or planned major surgery during this trial.

16. Has history of diabetes mellitus type 1 or type 2, including cases controlled with diet alone.

    *Note: history of isolated gestational diabetes is not an exclusion criterion.

17. Has history of thyroidectomy, or thyroid disease requiring medication in the last 12 months.

18. Has history of hypertension, even if medically controlled.

    *Note: Vital signs must be normal by protocol toxicity grading scale. In the event of an abnormal heart rate or blood pressure due to physiological variation or activity, the subject may rest for 10 minutes in a quiet room, and then blood pressure and/or heart rate re-measured. Repeated vital signs may be used to determine eligibility.

19. Received live attenuated vaccines from 30 days before first vaccination until 30 days after final vaccination*.

    *Not including licensed or authorized COVID-19 vaccines.

20. Received killed or inactivated vaccines from 14 days before first vaccination until 30 days after final vaccination*.

    *Not including licensed COVID-19 vaccines

21. Received experimental therapeutic agents within 3 months before first vaccination or plans to receive any experimental therapeutic agents during this trial*.

    *That that in the opinion of the investigator would interfere with safety or immunogenicity assessments.

22. Is currently participating or plans to participate in another clinical study which would involve receipt of the following:*

    * An investigational product, blood drawing, or an invasive medical procedure that would require administration of anesthetics, intravenous (IV) dyes, or removal of tissue during this trial and, in the opinion of the investigator, would interfere with safety or immunogenicity assessments.

    -Includes endoscopy, bronchoscopy, and administration of IV contrast.

23. Received blood products or immunoglobulin in the 3 months before study entry or planned use during this trial.

24. Donated a unit of blood or blood products within 8 weeks before Day 1 or plans to donate blood or blood products during this trial.

25. Has major psychiatric illness in the past 12 months that in the opinion of the investigator would preclude participation.

26. Has current alcohol use or current or past abuse of recreational or narcotic drugs by history as judged by the investigator to potentially interfere with study adherence.

27. Has a history of chronic urticaria.

28. Has tattoos, scars, or other marks on both deltoid areas which would, in the opinion of the investigator, interfere with assessment of the vaccination site.

29. Is a site employee* or staff who are paid entirely or partially by/through the OCRR contract for this trial, or staff who are supervised by the Principal Investigator (PI) or sub-investigators.

    *Including the PI, sub-investigators listed on Form FDA 1572 or Investigator of Record Form.

30. In the opinion of the investigator cannot communicate reliably, is unlikely to adhere to the requirements of this trial, or has any condition which would limit the ability to complete this trial.

31. Has history of Guillain-Barre syndrome, meningitis, encephalitis, neuroparalysis, transient paralysis, myelitis, retrobulbar neuritis, multiple sclerosis, vertigo, or visual disturbances.

32. Has a history of arterial or venous thrombosis, or thrombocytopenia that required medical attention.