Vaccine Information: ERVEBO

ERVEBO- zaire ebolavirus (strain kikwit-95) envelope glycoprotein injection, solution
Merck Sharp & Dohme LLC

1 INDICATIONS AND USAGE

ERVEBO® is indicated for the prevention of disease caused by Zaire ebolavirus in individuals 18 years of age and older.

1.1 Limitations of Use

• The duration of protection conferred by ERVEBO is unknown.
• ERVEBO does not protect against other species of Ebolavirus or Marburgvirus.
• Effectiveness of the vaccine when administered concurrently with antiviral medication, immune globulin (IG), and/or blood or plasma transfusions is unknown.

2 DOSAGE AND ADMINISTRATION

FOR INTRAMUSCULAR ADMINISTRATION ONLY.

2.1 Dosage

Administer 1 mL dose of ERVEBO.

2.2 Preparation

Thaw vial at room temperature until no visible ice is present. Do not thaw the vial in a refrigerator. Gently invert vial several times. The vaccine is a colorless to slightly brownish-yellow liquid with no particulates visible. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If either of these conditions exist, discard the vial.

Use the vaccine immediately after thawing. If not used immediately, the vaccine may be stored for 4 hours at room temperature (up to 25°C; 77°F) protected from light. DO NOT REFREEZE [see How Supplied/Storage and Handling (16)].

Withdraw the 1 mL dose of vaccine from the vial using a sterile needle and sterile syringe.

2.3 Administration

Administer a 1 mL dose of ERVEBO intramuscularly, preferably in the deltoid area of the non-dominant arm. Discard unused portion.

3 DOSAGE FORMS AND STRENGTHS

ERVEBO is a suspension for injection supplied as a 1 mL dose in single-dose vials.

4 CONTRAINDICATIONS

Do not administer ERVEBO to individuals with a history of a severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine, including rice protein [see Description (11)].

5 WARNINGS AND PRECAUTIONS

5.1 Management of Acute Allergic Reactions

Among 17,415 subjects vaccinated with ERVEBO in clinical trials, there were two reports of anaphylaxis [see Adverse Reactions (6.1)]. Monitor individuals for signs and symptoms of hypersensitivity reactions following vaccination with ERVEBO. Appropriate medical treatment and supervision must be available in case of an anaphylactic event following the administration of ERVEBO.

5.2 Limitations of Vaccine Effectiveness

Vaccination with ERVEBO may not protect all individuals. Vaccinated individuals should continue to adhere to infection control practices to prevent Zaire ebolavirus infection and transmission.

5.3 Immunocompromised Individuals

The safety and effectiveness of ERVEBO have not been assessed in immunocompromised individuals. The effectiveness of ERVEBO in immunocompromised individuals may be diminished. The risk of vaccination with ERVEBO, a live virus vaccine, in immunocompromised individuals should be weighed against the risk of disease due to Zaire ebolavirus.

5.4 Transmission

Vaccine virus RNA has been detected by RT-PCR in blood, saliva, urine, and fluid from skin vesicles of vaccinated adults. Transmission of vaccine virus is a theoretical possibility [see Pharmacokinetics (12.3)].

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.

The clinical development program for ERVEBO included clinical studies conducted in North America, Europe and Africa, in which 17,415 adults received a dose of ERVEBO. The number of subjects vaccinated with ERVEBO in double-blind, placebo-controlled trials was 1,712 and in open-label trials was 15,703.

In Study 1 (NCT02344407), conducted in Liberia (N=1,000), subjects were randomized 1:1 to receive ERVEBO or saline placebo. Subjects were assessed at Week 1 and Month 1 postvaccination for solicited local and systemic reactions. In a subset of subjects (n=201), joint symptoms and signs were also solicited during a Week 2 visit. Memory aids were not used and postvaccination temperatures were measured only at study visits. Unsolicited adverse events were collected through Month 1 postvaccination. The median age of subjects was 29 years, 63.6% were male and 100% were Black. Serious adverse events were monitored through 1 year postvaccination.

In Study 2 (NCT02503202), conducted in the United States, Canada and Spain (N=1,197), subjects were randomized to receive ERVEBO (n=1,061) or saline placebo (n=133). Subjects used a memory aid to record solicited local reactions from Days 1 to 5 postvaccination, and daily temperature measurements and solicited joint and skin events from Days 1 to 42 postvaccination. Unsolicited adverse reactions were collected through Day 42 postvaccination. The median age of subjects was 42 years; 46.8% were male; 67.9% were White, 29.2% were Black or African American, 1.4% were Multi-racial, 0.8% were Asian, 0.4% were American Indian or Alaska Native, and 0.3% were Native Hawaiian or Pacific Islander; 14.5% were Hispanic or Latino. Serious adverse events were monitored through 6 months postvaccination and a subset of subjects (n=511) were monitored through 24 months postvaccination.

In Study 3 (Pan African Clinical Trials Registry, PACTR201503001057193), an open-label cluster-randomized study conducted in the Republic of Guinea, 5,643 adult subjects received a dose of ERVEBO. The median age of vaccinated subjects was 37 years, 68% were male and 100% were Black. Serious adverse events were monitored through 84 days postvaccination.

In Study 4 (NCT02378753), a randomized open-label study conducted in Sierra Leone, 7,998 adult subjects received a dose of ERVEBO. The median age of subjects was 31 years, 63% were male; 99.8% were Black and 0.2% collectively were Multi-racial, Asian or White. Serious adverse events were monitored through 180 days postvaccination.

In Study 5 (Pan African Clinical Trials Registry, PACTR201503001057193), an open-label safety and immunogenicity trial conducted in vaccinated frontline workers in the Republic of Guinea, implemented as Part B of Study 3, 2,016 adult subjects received a dose of ERVEBO. The median age of vaccinated subjects was 30 years, 75% were male and 100% were Black. Serious adverse events were monitored through 85 days postvaccination.

Eight additional studies (NCT02269423, NCT02280408, NCT02374385, NCT02314923, NCT02287480, NCT02283099, NCT02296983) contributed to the assessment of serious adverse reactions.

Adverse Reactions

Table 1 presents the proportion of subjects reporting solicited adverse reactions in Study 1.

Table 1: Percentage of Subjects with Solicited Local and Systemic Adverse Reactions After Vaccination (Study 1)

	ERVEBO (%)	PLACEBO (%)
* Adverse reactions were solicited at 30 minutes, Week 1 and Month 1 postvaccination. † Adverse reactions were solicited at Week 1 and Month 1 postvaccination. ‡ In a subset of subjects (n=201), joint symptoms and signs were also solicited during a Week 2 visit.
Injection-site reactions *	N= 500	N= 500
Injection site pain	34.0	11.2
Local reactions (redness/swelling)	1.8	0.8
Systemic adverse reactions †	N= 498	N= 499
Headache	36.9	23.2
Feverishness	34.3	14.8
Muscle pain	32.5	22.8
Fatigue	18.5	13.4
Nausea	8.0	4.4
Joint pain/tenderness ‡	7.0	5.8
Rash	3.6	3.2
Abnormal sweating	3.2	2.6
Arthropathy (joint redness/warmth)‡	0.6	0.2
Joint swelling ‡	0.4	0.4
Joint stiffness ‡	0.4	0.2

In Study 1, 56.4% of subjects reported at least one of the solicited systemic adverse reactions listed in Table 1 within seven days after vaccination. With the exception of one subject who reported events of moderate intensity (causing greater than minimal interference with daily activity), all others reported events of mild intensity (causing no or minimal interference with daily activity).

Table 2 presents the proportion of subjects reporting solicited adverse reactions in Study 2.

Table 2: Percentage of Subjects with Solicited Local and Systemic Adverse Reactions After Vaccination (Study 2)

	ERVEBO (%)	Placebo (%)
* Adverse reactions were solicited Days 1 to 5 postvaccination. † Adverse reactions were solicited Day 1 through Day 42 postvaccination. ‡ Arthritis is a composite term that includes preferred terms of arthritis, monoarthritis, polyarthritis, osteoarthritis, joint swelling, or joint effusion. § Rash is a composite term that includes petechiae, purpura, rash, rash generalized, rash macular, rash papular and rash vesicular. ¶ Vesicular lesions include events reported as rash vesicular in the rash composite term and reported as blister.
Injection-site reactions *	N= 1051	N= 133
Injection-site pain	69.5	12.8
Injection-site swelling	16.5	3.0
Injection-site redness	11.9	1.5
Systemic adverse reactions †	N= 1051	N= 133
Joint pain	17.9	3.0
Arthritis (composite term)‡	4.7	0.0
Rash (composite term)§	3.8	1.5
Vesicular lesions ¶	1.5	0.0

In Study 2, 29 subjects (2.8%) reported injection-site pain of severe intensity. Severe arthritis (arthritis and joint swelling) was reported by 8 subjects (0.8%) and severe arthralgia was reported by 14 subjects (1.3%). In this study, severe events were defined as incapacitating with inability to work or do usual activity.

Unsolicited Adverse Reactions

In Study 2, the unsolicited adverse reaction of chills was reported in 7.3% of ERVEBO recipients compared to 0% of placebo recipients. Paresthesia was reported by 1.4% of ERVEBO recipients compared to 0% of those who received placebo in this study.

Arthralgia and Arthritis

Arthralgia was reported to occur in 7% to 40% of vaccine recipients in blinded, placebo-controlled studies. Arthralgia was generally reported in the first few days following vaccination, was of mild to moderate intensity, and resolved within one week after onset. Severe arthralgia, defined as preventing daily activity, was reported in up to 3% of subjects.

Arthritis (including events of arthritis, joint effusion, joint swelling, osteoarthritis, monoarthritis or polyarthritis) was reported to occur in 0% to 24% of subjects in blinded, placebo-controlled studies in which subjects received ERVEBO or a lower dose formulation, with all but one study reporting arthritis in <5% of subjects. Most occurrences of arthritis were reported within the first few weeks following vaccination, were of mild to moderate intensity, and resolved within several weeks after onset. In one study conducted in Switzerland (NCT02287480), 102 subjects received ERVEBO or a lower dose formulation. In this study, arthritis was reported to occur in 24% of subjects and severe arthritis, defined as preventing daily activity, in 12% of subjects. Joint effusion samples were obtained from three subjects and all three tested positive for vaccine virus RNA by RT-PCR. Of all 24 subjects with arthritis in this study, six subjects reported recurrent or prolonged joint symptoms lasting up to 2 years following vaccination, the longest follow-up period.

Rash

Rash was reported to occur after administration of ERVEBO in blinded, placebo-controlled studies, with all but one study reporting rash in <9% of subjects. In one study (NCT02287480), rash was reported to occur in 25% (n=4) of ERVEBO recipients and 7.7% (n=1) of placebo recipients. In this study, cutaneous vasculitis was reported in two subjects who received a lower dose formulation, neither of whom had evidence of systemic vasculitis. Vesicular fluid and skin biopsy samples taken from some subjects reporting rash have tested positive for vaccine virus RNA by RT-PCR.

Decreases in Lymphocytes and Neutrophils

White blood cell counts were assessed in 697 subjects who received ERVEBO. Decreases in lymphocytes were reported in up to 85% of subjects and decreases in neutrophils were reported in up to 43% of subjects. No associated infections were reported.

Serious Adverse Reactions

In 17,415 ERVEBO recipients, two serious adverse reactions of pyrexia were reported as vaccine-related. In addition, two serious adverse reactions of anaphylaxis were reported as vaccine-related. None of these serious adverse reactions were fatal.