Chimpanzee Adenovirus and Self-Amplifying mRNA Prime-Boost Prophylactic Vaccines Against SARS-CoV-2 in Healthy Adults

This is a multicenter, US-only, phase 1, open-label, dose escalation, non-randomized study of the safety, tolerability, and immunogenicity of investigational ChAd and SAM SARS-CoV-2 vaccines in healthy adult subjects. Homologous and heterologous prime-boost vaccination schedules (Stage 1), as well as boost(s) after receipt of COVID-19 EUA/licensed vaccines (Stage 2) will be examined. Subjects' willingness to receive ChAd vaccines will be assessed and documented at the time of informed consent and considered to determine group assignments. This phase 1 study will enroll 17 Stage 1 and up to 118 Stage 2 subjects. Eligible subjects will be enrolled in different groups based on their age (18-60 years old and \>60 years old) and their EUA/licensed COVID-19 vaccination status. A sentinel approach with 72-hour (Stage 1, and Stage 2, Groups 5, 6, 8-10, 12, 13-15) or 7-day observation times (Groups 7 and 11) will be used, before recruiting the remainder of each dose escalation group. Decisions about dose escalation will be determined by the SSC with consultation with the DSMB as needed after all subjects in each group have been observed through Day 8 post first study vaccination. All subjects will be followed through 12 months after their last study vaccination. Vaccinated subjects will be carefully monitored for exposure and infection to SARS-CoV-2 throughout the study. Escalation to the highest dose (10 µg) of SAM-S-TCE in younger subjects will proceed only following safety assessments of the 10 µg dose in older subjects for a period of 28 days post-vaccination. In addition, the dosage of SAM-S-TCE given as a double boost to subjects previously vaccinated with the Johnson \& Johnson/Janssen Ad26 COVID-19 EUA/licensed vaccine in Groups 8A, 8B, and 12A, 12B will be determined based on the dose escalation reactogenicity and immunogenicity results in Groups 5-7 and 9-11, respectively. After protocol version 9.0 was implemented, it was decided not to enroll subjects into Groups 7 and 8 because of competing priorities and predicted difficulties enrolling into these two groups.

The primary objectives of this study are 1) To assess the safety and tolerability of different doses of ChAd-S or ChAd-S-TCE, and SAM-S or SAM-S-TCE when administered as prime-boost in healthy naïve adult subjects, 2) To assess the safety and tolerability of different doses of ChAd-S or ChAd-S-TCE, and SAM-S or SAM-S-TCE when administered as first or second boost in healthy adult subjects previously vaccinated with an mRNA or adenoviral-vectored COVID-19 EUA/licensed vaccine.

This is a multicenter, US-only, phase 1, open-label, dose escalation, non-randomized study of the safety, tolerability, and immunogenicity of investigational ChAd and SAM SARS-CoV-2 vaccines in healthy adult subjects. Homologous and heterologous prime-boost vaccination schedules (Stage 1), as well as boost(s) after receipt of COVID-19 EUA/licensed vaccines (Stage 2) will be examined. Subjects' willingness to receive ChAd vaccines will be assessed and documented at the time of informed consent and considered to determine group assignments. This phase 1 study will enroll 17 Stage 1 and up to 118 Stage 2 subjects. Eligible subjects will be enrolled in different groups based on their age (18-60 years old and \>60 years old) and their EUA/licensed COVID-19 vaccination status. A sentinel approach with 72-hour (Stage 1, and Stage 2, Groups 5, 6, 8-10, 12, 13-15) or 7-day observation times (Groups 7 and 11) will be used, before recruiting the remainder of each dose escalation group. Decisions about dose escalation will be determined by the SSC with consultation with the DSMB as needed after all subjects in each group have been observed through Day 8 post first study vaccination. All subjects will be followed through 12 months after their last study vaccination. Vaccinated subjects will be carefully monitored for exposure and infection to SARS-CoV-2 throughout the study. Escalation to the highest dose (10 µg) of SAM-S-TCE in younger subjects will proceed only following safety assessments of the 10 µg dose in older subjects for a period of 28 days post-vaccination. In addition, the dosage of SAM-S-TCE given as a double boost to subjects previously vaccinated with the Johnson \& Johnson/Janssen Ad26 COVID-19 EUA/licensed vaccine in Groups 8A, 8B, and 12A, 12B will be determined based on the dose escalation reactogenicity and immunogenicity results in Groups 5-7 and 9-11, respectively. After protocol version 9.0 was implemented, it was decided not to enroll subjects into Groups 7 and 8 because of competing priorities and predicted difficulties enrolling into these two groups.

The primary objectives of this study are 1) To assess the safety and tolerability of different doses of ChAd-S or ChAd-S-TCE, and SAM-S or SAM-S-TCE when administered as prime-boost in healthy naïve adult subjects, 2) To assess the safety and tolerability of different doses of ChAd-S or ChAd-S-TCE, and SAM-S or SAM-S-TCE when administered as first or second boost in healthy adult subjects previously vaccinated with an mRNA or adenoviral-vectored COVID-19 EUA/licensed vaccine. The secondary objective of this study is to assess the humoral immunogenicity of ChAd-S or ChAd-S-TCE, and SAM-S or SAM-S-TCE.

Eligibility Criteria:
Inclusion Criteria:

Subjects eligible to participate in this trial must meet all of the following inclusion criteria:

1. Provide written informed consent prior to initiation of any study procedures
2. Able and willing (in the investigator's opinion) to comply with all study requirements
3. Are men or non-pregnant women aged 18 years or older at enrollment
4. Are in good health\*

   \*As defined by absence of clinically significant medical conditions defined by the CDC as increasing risk for severe corona virus disease-19 (COVID-19) (see exclusion criteria), or other acute or chronic medical conditions determined by medical history, physical examination (PE), screening laboratory test results, and/or clinical assessment of the investigator that are either listed as exclusion criteria below or in the opinion of the investigator would increase risk for study participation or affect the assessment of the safety of subjects. Chronic medical conditions should be stable for the last 60 days (no hospitalizations, emergency room or urgent care for condition, or invasive medical procedures). Any prescription change that is due to change of health care provider, insurance company, etc., or done for financial reasons, and in the same class of medication, will not be considered a deviation of this inclusion criterion. Any change in prescription medication due to improvement of a disease outcome, as determined by the participating site PI or appropriate sub- investigator, will not be considered a deviation of this inclusion criterion. Subjects may be on chronic or as needed (prn) medications if, in the opinion of the participating site PI or appropriate sub-investigator, they pose no additional risk to subject safety or assessment of reactogenicity and immunogenicity, and do not indicate a worsening of medical diagnosis/condition. Similarly, medication changes in the 60 days prior to enrollment as well as subsequent to enrollment and study vaccination are acceptable provided the change was not precipitated by deterioration in the chronic medical condition, and there is no anticipated additional risk to the subject or interference with the evaluation of responses to study vaccination.
5. Agree to refrain from blood donation during the course of the study
6. Plan to remain living in the area for the duration of the study
7. Women of childbearing potential (WOCBP)\* must plan to avoid pregnancy for at least 60 days after the last study vaccination and be willing to use an adequate method of contraception\*\* consistently for 30 days prior to first study vaccine and for at least 60 days after the last study vaccine.

   \*Not sterilized via bilateral oophorectomy, tubal ligation/salpingectomy, hysterectomy, or successful Essure (R) placement (permanent, non-surgical, non-hormonal sterilization with documented radiological confirmation test at least 90 days after the procedure); still menstruating; or \< 1 year has passed since the last menses if menopausal

   \*\*Acceptable methods of birth control include the following: oral contraceptives, injection hormonal contraceptive, implant hormonal contraceptive, hormonal patch, intrauterine device, spermicidal products and barrier methods (such as cervical sponge, diaphragm, or condom with spermicide), abstinence, monogamous with a vasectomized partner, non-male sexual relationship
8. Women of childbearing potential must have a negative urine or serum pregnancy test within 24 hours prior to each study vaccination
9. Vital signs within acceptable ranges:

   * Pulse \> 50 and = / \< 100 beats per minute
   * Systolic blood pressure (BP) = / \< 140 millimeters of mercury (mmHg)
   * Diastolic BP = / \< 90 mmHg
   * Oral temperature \< 37.8 degrees Celsius (100.0 degrees Fahrenheit)
10. Clinical screening lab evaluations (white blood cell (WBC), hemoglobin (HgB), platelets (PLT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (T Bili), creatine kinase (CK), serum creatinine (Cr) and prothrombin time (PT)/partial thromboplastin time (PTT)) are within acceptable normal reference ranges at the clinical lab being used\* \*With the exception that ALT, AST, ALP, and creatinine values that are below the reference range will not be exclusionary as these values below reference range are clinically insignificant. Any other screening lab value outside the reference range that is thought to be clinically insignificant by a site investigator must be discussed with the DMID Medical Officer prior to enrollment.
11. Must agree to genetic testing and storage of samples for secondary research
12. Received at least 2 doses of EUA/licensed mRNA vaccines or at least 1 dose of Ad26 vaccine followed by an mRNA booster, with the last COVID-19 vaccine dose given at least 112 days prior to enrollment (Stage 2 only), as confirmed via CDC vaccination card or other appropriate documentation. Subjects may or may not have been previously infected with SARS-CoV-2.

A subject must meet all of the following criteria to be eligible for leukapheresis:

1. Written informed consent for leukapheresis is provided
2. Weight \> / = 110 pounds
3. Screening laboratory evaluations are within acceptable ranges at the site where the leukapheresis procedure will be performed
4. Negative urine or serum pregnancy test at screening and on the day of the leukapheresis procedure for women of childbearing potential
5. Adequate bilateral antecubital venous access
6. No use of blood thinners, aspirin, or nonsteroidal anti-inflammatory drugs (NSAIDs) at least 5 days before the leukapheresis procedure

Exclusion Criteria:

Subjects eligible to participate in this trial must not meet any of the following exclusion criteria:

1. History of prior confirmed (PCR or antigen test positive) COVID-19 less than 112 days prior to enrollment.
2. Positive for anti-nucleoprotein SARS-CoV-2 specific antibody by enzyme-linked immunosorbent assay (ELISA) and had the history of upper respiratory illness (URI) compatible with COVID-19 during the 112 days prior to enrollment (seropositivity without a history of URI during the 112 days prior to enrollment will be considered remotely infected persons eligible for enrollment).
3. Positive nasal swab polymerase chain reaction (PCR) at screening.
4. Body mass index (BMI) \> 30 kg/m\^2 for Stage 1 participants and BMI \> 35 kg/m\^2 for Stage 2 participants.
5. Presence of medical comorbidities that would place the subject at increased risk for severe COVID-19\*

   \*Chronic kidney disease, chronic lung disease (including moderate-to-severe asthma), chronic heart disease (heart failure, coronary artery disease or cardiomyopathies), cerebrovascular disease, diabetes mellitus, chronic liver disease, sickle cell disease
6. Increased risk of occupational exposure to SARS-CoV-2 (healthcare workers and emergency response personnel)\*

   \*Applies to Stage 1 participants only
7. Prior receipt of an approved/licensed or investigational SARS-CoV-2 vaccine (including under EUA)\*, approved or investigational adenovirus-vectored vaccines\*\*, or any other approved or investigational vaccine likely to impact the interpretation of the trial data.

   \*Exclusion of prior receipt of EUA/licensed COVID-19 vaccines applies to Stage 1 participants only.

   \*\*With the exception of prior receipt of EUA/licensed Johnson \& Johnson/Janssen Ad 26 COVID-19 vaccine which is permitted for Groups 8A, 8B, 12A, and 12B.
8. On current treatment or prevention agents with activity against SARS-CoV-2
9. Current smoking or vaping or history of smoking or vaping in prior year\*

   \*Applies to Stage 1 participants only
10. Breastfeeding, pregnant, or planning to become pregnant during the course of the study.
11. Participation in another research study involving receipt of an investigational product in the 60 days preceding enrolment or planned use during the study period
12. Receipt or planned receipt of any live, attenuated vaccine within 28 days before or after study vaccination
13. Receipt or planned receipt of any subunit or killed vaccine within 14 days before or after vaccination
14. Administration of immunoglobulins and/or any blood products within the three months preceding the planned administration of first study vaccination or at any time during the study
15. Any confirmed or suspected immunosuppressive or immunodeficient state, including human immunodeficiency virus (HIV) infection, asplenia, recurrent, severe infections and chronic (more than 14 continuous days) immunosuppressant medication within the past 6 months (inhaled, ophthalmic, and topical steroids are allowed)
16. History of allergic disease or reactions likely to be exacerbated by any component of the vaccine, including urticaria, respiratory difficulty or abdominal pain (or any immediate allergic reaction of any severity to polysorbate due to potential cross-reactive hypersensitivity with the polyethylene glycol component of the vaccine)
17. Any history of hereditary angioedema, acquired angioedema, or idiopathic angioedema
18. Any history of anaphylaxis, including but not limited to reaction to vaccination
19. Any history of severe allergic drug reaction
20. History of cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ)
21. History of serious ongoing, unstable psychiatric condition that in the opinion of the investigator would interfere with study participation
22. Seizure in the past 3 years or treatment for seizure disorder in the past 3 years
23. Bleeding disorder (e.g., factor deficiency, coagulopathy, or platelet disorder), or prior history of significant bleeding or bruising following IM injections or venipuncture or family history of bleeding disorder
24. Recent (within the past 3 months) surgery, immobility, chronic infection, or head trauma that could increase the risks of thrombosis.
25. Suspected or known current alcohol abuse. Suspected or known drug abuse in the 5 years preceding enrollment
26. Seropositive for HIV, hepatitis B surface antigen (HBsAg), or seropositive for hepatitis C virus (antibodies to HCV)
27. Have an acute illness\* within 72 hours prior to study vaccination

    \*An acute illness which is nearly resolved with only minor residual symptoms remaining is allowable if, in the opinion of the site PI or appropriate sub-investigator, the residual symptoms will not interfere with the ability to assess safety parameters as required by the protocol
28. History of venous or arterial thrombosis or any known thrombophilic condition including heparin-induced thrombocytopenia (HIT) or family history of thrombosis.
29. History of myocarditis or pericarditis.
30. History of Guillain-Barre Syndrome (GBS).
31. Receiving heparin treatment or on medications associated with increased risk of bleeding or thrombosis.
32. Any other condition that in the opinion of the investigator would pose a health risk to the participant if enrolled or could interfere with evaluation of the trial vaccine or interpretation of study results