Safety and Immunogenicity of CRV-101 Vaccine for the Prevention of Herpes Zoster in Adults Aged 50 Years and Older

In the first part of the trial, participants will be randomized 1:1:1 to amezosvatein high antigen dose (Arm A), amezosvatein low antigen dose (B), or Shingrix (C). In the second part of the trial, participants will be randomized 5:1 to receive amezosvatein adjuvant dose D or Shingrix (E), adjuvant dose F or Shingrix (G), or adjuvant dose H or Shingrix (I). In the third part of the trial, participants will be randomized 3:1 to receive amezosvatein adjuvant dose J or Shingrix (K) or amezosvatein adjuvant dose L or Shingrix (M). Both study vaccines, amezosvatein and Shingrix, will be administered by intramuscular injection on Month 0 and Month 2. Safety, reactogenicity, and immunogenicity analysis will be performed overall and by age group. Participants will be followed for safety, immunogenicity, and herpes zoster cases from Day 0 to the main study end (Month 14), and through the long-term follow up (LTFU) extension period of up to 5 additional years.

Inclusion criteria

Participants are eligible to be included in the study only if all of the following criteria apply:

• Male and non-pregnant female participant must be ≥50 years of age inclusive, at the time of signing the informed consent.

• Arms A, B, C, J, K, L, and M will enroll participants ≥50 years of age
• Arms D, E, F, G, H, and I will enroll participants ≥50 to <70 years of age
• Participants who are healthy as determined by medical evaluation including comprehensive medical history, comprehensive physical examination, vital signs*, and screening laboratory tests conducted no more than 30 days prior to first study injection administration (Day 0).

• Vital signs within grade 1 on the severity grading scale, excluding temperature, are allowed. If vital sign parameter meets grade 2 criteria, then subject must be excluded. Vital signs may be repeated 3 times after a period of rest as needed if transient abnormal fluctuation is suspected.
• (Applicable only for arms A through I) Completed an Emergency Use Authorization (EUA) or Conditional Marketing Authorization or licensed initial COVID-19 vaccine series (as applicable) ≥30 days prior to enrollment (i.e., at least 30 days prior to the Day 0 visit).
• Screening laboratory values [sodium, potassium, blood urea nitrogen (BUN), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), total bilirubin, alkaline phosphatase, creatinine, random glucose, white blood cell count with differential, hemoglobin, and platelet count] must be within normal ranges or considered not clinically significant by the PI.**
• Negative HIV 1/2 antibody, hepatitis B surface antigen (HBsAg), and hepatitis C virus (HCV) antibody at screening. If HIV 1/2 antibody is positive, and confirmation testing is negative the participant may be enrolled.
• Normal urinalysis or, if abnormal, urinalysis determined to be not clinically significant by the PI at screening.**

• Screening laboratory values that are abnormal but are considered abnormal due to an acute illness or process may be repeated once. Careful consideration regarding enrolling subjects with screening lab values meeting grade 2 severity that are considered not clinically significant must be made as there is less room for fluctuations to increase to gr ade 3 (severe) lab events.
• A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:

• Is a woman of nonchildbearing potential (WONCBP). OR
• Is a woman of childbearing potential (WOCBP) and using an acceptable contraceptive method as defined below during the 30 days prior to Day 0 (i.e., the first study vaccine) and is willing to continue to do so during the study until at least 90 days after the last dose of study vaccine, and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relation to the timing of the first dose of study vaccine.
• A WOCBP must have a negative serum pregnancy test at screening and a negative urine pregnancy test on the day of each study vaccine (prior to vaccination). If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.

WONCBP is as defined as

• Postmenopausal: A postmenopausal state is defined as least 12 months of spontaneous amenorrhea.
• Permanently sterile: Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal occlusion/ligation procedures, bilateral oophorectomy, and successful Essure® placement (permanent, non-surgical, non-hormonal sterilization) with documented radiological confirmation test at least 90 days after the procedure, and still menstruating or <1 year since of the last menses if menopausal.

WOCBP is defined as

• Any woman or adolescent who has begun menstruation. Acceptable contraception methods include, but are not limited to, sexual abstinence, monogamous relationship with vasectomized partner who has been vasectomized for 6 months or more prior to the participant receiving study product, barrier methods such as condoms or diaphragms with spermicide or foam, effective intrauterine devices, NuvaRing®, and licensed hormonal methods such as implants, injectables, or oral contraceptives ("the pill").
• Capable of understanding and giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol prior to any screening procedures.
• Willing to abstain from donating whole blood or blood derivatives until after Day 84 visit, and within 60 days prior to each study visit after Day 84.
• Be able and willing to participate in all study visits and be reachable by telephone or personal contact by the study site personnel.
• Participants who the investigator believes will comply with the requirements of the protocol (e.g., completion of the diary cards, return for follow-up visits, have regular contact to allow evaluation during the study).
• Capable of understanding and completing diary card. Arms A, B, and C use electronic diary and require access to web browser. Arms D through M use paper diary

Exclusion criteria

Participants are excluded from the study if any of the following criteria apply:

• History of herpes zoster (shingles).
• History or presence of acute or chronic illness (including cardiovascular, pulmonary, neurological, hepatic, rheumatic, hematological, metabolic, gastrointestinal, endocrinologic or renal disorders, or uncontrolled hypertension) which in the opinion of the Principal Investigator, may interfere with the evaluation of the safety or immunogenicity of the vaccine.
• History of autoimmune disease or suspected immunosuppressive or immunodeficient condition resulting from disease (e.g., malignancy, HIV infection) or immunosuppressive/cytotoxic therapy (e.g., medications used during cancer chemotherapy, organ transplantation, or to treat autoimmune disorders) that is likely to affect the immune response to vaccination as determined by the PI.
• Rash, tattoos, or any other dermatological condition that could adversely affect the vaccine injection site or interfere with its evaluation.
• Abnormal blood pressure >150 mm Hg systolic or >95 mm Hg diastolic prior to first study injection administration (Day 0).***

*** If abnormal, BP may be repeated up to 3 times after a rest period of 5 minutes between each measurement.

• History of significant psychiatric illness (including history of suicidal ideation or attempt) with or without current medication.
• BMI ≥40kg/m2 at screening (where BMI >34.9 kg/m2, clinically-significant abnormal serum glucose at screening determined by the PI, or clinically-significant diseases or medical conditions, as determined by the PI, is exclusionary.)
• Significant underlying illness that in the opinion of the investigator would be expected to prevent completion of the study (e.g., life-threatening disease likely to limit survival to less than 4 years).
• Acute disease and/or fever at the time of enrollment (Day 0).

• Fever is defined as body temperature ≥38 °C (100.4 °F); oral acquisition will be the preferred route for recording temperature throughout this study.
• Participants with a minor illness (such as mild diarrhea or mild upper respiratory infection) without fever may be enrolled after resolution of the minor illness, at the discretion of the investigator.
• Immunized with a vaccine against herpes zoster (Zostavax®, Shingrix®, other licensed or investigational HZ vaccine).
• Prior varicella vaccination at any time.
• Received any vaccine within 30 days prior to enrollment (Day 0) or received any non-investigational immunizations while on study except for seasonal influenza, pneumococcal vaccines, other vaccines per the ACIP recommendations, or any licensed or emergency use authorization or conditional marketing authorized COVID-19 booster. Administration of these immunizations must not occur until 30 days after the final study vaccination and completion of the Day 84 immunology blood draw and must not occur within the 30 days prior to each on-study immunology blood draw after Day 84. Receipt of any VZV vaccine is prohibited on the study.
• Use of any medication that, in the opinion of the Principal Investigator, may interfere with the evaluation of the safety or immunogenicity of the vaccine.
• (a) Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs (e.g., oral or injected steroids, such as prednisone; high-dose inhaled steroids; biologics (e.g., tumor necrosis factor [TNF] inhibitor, or other cytokine inhibitors within 14 days of Day 0 through Day 84, and within 14 days of each on study immunogenicity blood draw after Day 84; Exclusionary corticosteroid administration is defined as prednisone >20 mg/day (or equivalent) for any frequency; low-dose inhaled and topical and ocular steroids are allowed; (b) or cytotoxic therapies, such as chemotherapy drugs or radiation, from 180 days prior to enrollment, during the study through Day 421.

Participants who meet this criterion from 14a and 14b after Day 56, should continue to be followed for safety and immunogenicity but will not be in included in the per protocol population from the date of meeting the criterion.

• Received a blood transfusion, platelets, plasma, or immunoglobulin 90 days prior to first dose of study vaccine (Day 0) or planned administration of such products during the study.
• Donated blood products (platelets, whole blood, plasma, etc.) within 60 days prior to enrollment (Day 0).
• Participation in another experimental protocol which includes the receipt of any investigational products/vaccines or devices within 90 days prior to enrollment (Day 0) in this study, or planned participation in another experimental protocol which includes investigational product/vaccine or device receipt during the study period through D421*. After the D421 visit, participation in another clinical study and with concurrent receipt of another experimental investigational product/vaccine or device is allowed with medical monitor approval. Any other investigational product/vaccine with immune modulating effect which would complicate the assessment of humoral and cellular responses, including investigational vaccines, must not be used 60 days prior to each LTFU extension year visit. Receipt of another experimental VZV vaccine or HSV vaccine is prohibited on the study.

*Prior to Day 421, concurrent participation in a study which previously included investigational product/vaccine receipt but is no longer receiving investigational products/vaccine, such as in an observational phase of the other study, is allowed.

• History of previous anaphylaxis or severe allergic reaction to vaccines or sensitivity to any of the study vaccines, or components thereof, or drug or other allergy that, in the opinion of the investigator, contraindicates participation in the study.
• Known or suspected alcohol or drug abuse within 5 years prior to enrollment (Day 0).
• ≥20 pack-years for a current smoker or a former smoker at screening.
• Unlikely to cooperate with the requirements of the study protocol, or deemed unreliable in attending study visits, or otherwise determined by the investigator not to be a good candidate to participate in this study.

[protocol v8.0]