These highlights do not include all the information needed to use JYNNEOS safely and effectively. See full prescribing information for JYNNEOS.JYNNEOS (Smallpox and Monkeypox Vaccine, Live, Non-replicating) suspension for subcutaneous injectionInitial U.S. Approval: 2019

1 INDICATIONS AND USAGE

JYNNEOS is a vaccine indicated for prevention of smallpox and monkeypox disease in adults 18 years of age and older determined to be at high risk for smallpox or monkeypox infection.

2 DOSAGE AND ADMINISTRATION

For subcutaneous injection only.

2.1 Dose and Schedule

Administer two doses (0.5 mL each) of JYNNEOS 4 weeks apart.

2.2 Preparation and Administration

Allow the vaccine to thaw and reach room temperature before use. Once thawed, the vaccine may be kept at +2°C to +8°C (+36°F to +46°F) for 4 weeks. Do not refreeze.

When thawed, JYNNEOS is a milky, light yellow to pale white colored suspension.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 exists, the vaccine should not be administered.

Swirl the vial gently before use for at least 30 seconds. Withdraw a dose of 0.5 mL into a sterile syringe for injection.

Administer JYNNEOS by subcutaneous injection, preferably into the upper arm.

3 DOSAGE FORMS AND STRENGTHS

JYNNEOS is a suspension for injection. Each dose (0.5 mL) is supplied in a single‑dose vial.

5 WARNINGS AND PRECAUTIONS

5.1 Severe Allergic Reactions

Appropriate medical treatment must be available to manage possible anaphylactic reactions following administration of JYNNEOS.

Persons who experienced a severe allergic reaction following a previous dose of JYNNEOS or following exposure to any component of JYNNEOS may be at increased risk for severe allergic reactions after JYNNEOS. The risk for a severe allergic reaction should be weighed against the risk for disease due to smallpox or monkeypox.

5.2 Syncope

Syncope (fainting) has been reported following vaccination with JYNNEOS. Procedures should be in place to avoid injury from fainting.

5.3 Altered Immunocompetence

Immunocompromised persons, including those receiving immunosuppressive therapy, may have a diminished immune response to JYNNEOS.

5.4 Limitations of Vaccine Effectiveness

Vaccination with JYNNEOS may not protect all recipients.

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 with rates in the clinical trials of another vaccine, and may not reflect the rates observed in practice. There is the possibility that broad use of JYNNEOS could reveal adverse reactions not observed in clinical trials.

The overall clinical trial program included 22 studies and a total of 7,859 individuals 18 through 80 years of age who received at least 1 dose of JYNNEOS (7,093 smallpox vaccine-naïve and 766 smallpox vaccine-experienced individuals).

Solicited Adverse Reactions

Solicited Adverse Reactions in Smallpox Vaccine-Naïve Individuals:

The safety of JYNNEOS in smallpox vaccine-naïve individuals was evaluated in Study 1 [1], a randomized, double-blind, placebo-controlled study conducted in the US in which vaccinia-naïve adults ages 18 to 40 years received either two doses of JYNNEOS (N=3003), or two injections of Tris-Buffered Saline (placebo, N=1002) four weeks apart.

In the total study population, the mean age was 28 years; 47.9% of the subjects were men; 77.4% were white/Caucasian, 17.8% black/African American, 1.9% Asian, 0.5% American Indian/Alaska Native, 0.4% Native Hawaiian/Other Pacific, 1.9% other racial groups; and 11.4% of subjects were of Hispanic/Latino ethnicity. The demographic compositions of JYNNEOS and placebo groups were similar.

In Study 1, subjects were monitored for local and systemic adverse reactions using diary cards for an 8-day period starting on the day of each vaccination. The frequencies of solicited local and systemic adverse reactions following any dose of JYNNEOS are presented in Table 1.

In Study 1, the majority of solicited local and systemic adverse reactions reported with JYNNEOS had a median duration of 1 to 6 days. In general, there were similar proportions of subjects reporting solicited local or systemic reactions of any severity after Dose 2 of JYNNEOS compared with Dose 1, with the exception of injection site pain, which was more commonly reported following Dose 1 (79.3%) than Dose 2 (69.9%).

Solicited Adverse Reactions in Persons Previously Vaccinated with a Smallpox Vaccine:

Three studies (Study 2, Study 3, and Study 4, [2-4]) conducted in the US and Germany evaluated the safety of JYNNEOS in 409 persons previously vaccinated with a smallpox vaccine who received one or two doses of JYNNEOS (mean age 39 years, range 20-80 years; 59% women; 98.8% white/Caucasian; 0.7% Asian; 0.5% black/African American). Subjects were monitored for local and systemic adverse reactions using diary cards for an 8-day period starting on the day of each vaccination. Across all three studies, solicited local adverse reactions reported following any dose of JYNNEOS were redness (80.9%), pain (79.5%), induration (70.4%), swelling (67.2%), and itching (32.0%) at the injection site; solicited systemic adverse reactions reported following any dose of JYNNEOS were fatigue (33.5%), headache (27.6%), muscle pain (21.5%), nausea (9.8%), chills (0.7%), and fever (0.5%).

Solicited Adverse Reactions in HIV-infected Individuals:

The safety of JYNNEOS in HIV-infected individuals was evaluated in Study 5 [5], an open label trial conducted in the US that included 351 HIV-infected smallpox vaccine-naïve subjects, 131 HIV-infected subjects who previously received smallpox vaccine, 88 non-HIV-infected smallpox vaccine-naïve subjects and 9 non-HIV-infected subjects who had previously received a smallpox vaccine. The racial/ethnic and gender compositions of HIV-infected smallpox vaccine-naïve subjects and those who had previously received smallpox vaccine were similar and overall were 17.0% women; 45.8% white/Caucasian; 0.4% Asian; 33.2% black/African American; 19.0% Hispanic/Latino ethnicity; the HIV-infected smallpox vaccine-naïve group tended to be younger (mean age 37 years) compared to those who had previously received a smallpox vaccine (mean age 45 years). Subjects had CD4 counts ≥ 200 and ≤ 750 cells/µL at study entry.

Solicited local and systemic adverse reactions were reported at similar or lower frequencies in HIV-infected smallpox vaccine-naïve subjects as compared to those seen in non-HIV-infected smallpox vaccine-naïve individuals in this study.

In HIV-infected subjects with previous smallpox vaccine exposure, fever and chills were reported in 1.5% and 8.4% of subjects respectively. Frequencies of other solicited local and general adverse reactions in this population were similar to those reported in Studies 2-4 in non-HIV-infected subjects who had previously received smallpox vaccination.

Solicited Adverse Reactions in Individuals with Atopic Dermatitis:

The safety of JYNNEOS in smallpox vaccine-naïve subjects with currently active or a history of atopic dermatitis (AD) was evaluated in a multicenter, open-label clinical study (Study 6 [6]) conducted in the US and Mexico that included 350 subjects with AD and 282 subjects without AD. In the overall study the mean age of subjects was 27 years (range 18-42 years), and subjects were 59.0% women, 39.4% white/Caucasian, 10.9% Asian, 9.0% black/African American, 2.2% Other, and 38.4% Hispanic/Latino ethnicity. Demographic compositions were similar between subjects with and without AD. In subjects with AD, solicited local and systemic adverse reactions were reported at similar frequencies as those in subjects without AD in this study, with the exception of redness (61.2% with AD vs. 49.3% without AD), swelling (52.2% with AD vs. 40.8% without AD), chills (15.9% with AD vs. 7.8% without AD) and headache (47.2% with AD vs. 34.8% without AD).

Serious Adverse Events

The integrated analyses of serious adverse events (SAEs) pooled safety data across 22 studies, which included a total of 7,093 smallpox vaccine-naïve subjects and 766 smallpox vaccine-experienced subjects who received at least 1 dose of JYNNEOS and 1,206 smallpox vaccine-naïve subjects who received placebo only. SAEs were monitored from the day of the first study vaccination through at least 6 months after the last study vaccination.

Among the smallpox vaccine-naïve subjects, SAEs were reported for 1.5% of JYNNEOS recipients and 1.1% of placebo recipients. Among the smallpox vaccine-experienced subjects enrolled in studies without a placebo comparator, SAEs were reported for 2.3% of JYNNEOS recipients. Across all studies, a causal relationship to JYNNEOS could not be excluded for 4 SAEs, all non-fatal, which included Crohn’s disease, sarcoidosis, extraocular muscle paresis and throat tightness.

Cardiac Adverse Events of Special Interest

Evaluation of cardiac adverse events of special interest (AESIs) included any cardiac signs or symptoms, ECG changes determined to be clinically significant, or troponin-I elevated above 2 times the upper limit of normal. In the 22 studies, subjects were monitored for cardiac-related signs or symptoms through at least 6 months after the last vaccination.

The numbers of JYNNEOS and placebo recipients, respectively, with troponin-I data were: baseline level (6,376 and 1,203); level two weeks after first dose (6,279 and 1,166); level two weeks after second dose (1,683 and 193); unscheduled visit, including for clinical evaluation of suspected cardiac adverse events (500 and 60).

Cardiac AESIs were reported to occur in 1.3% (95/7,093) of JYNNEOS recipients and 0.2% (3/1,206) of placebo recipients who were smallpox vaccine-naïve. Cardiac AESIs were reported to occur in 2.1% (16/766) of JYNNEOS recipients who were smallpox vaccine-experienced. The higher proportion of JYNNEOS recipients who experienced cardiac AESIs was driven by 28 cases of asymptomatic post-vaccination elevation of troponin-I in two studies: Study 5, which enrolled 482 HIV-infected subjects and 97 healthy subjects, and Study 6, which enrolled 350 subjects with atopic dermatitis and 282 healthy subjects. An additional 127 cases of asymptomatic post-vaccination elevation of troponin-I above the upper limit of normal but not above 2 times the upper limit of normal were documented in JYNNEOS recipients throughout the clinical development program, 124 of which occurred in Study 5 and Study 6. Proportions of subjects with troponin-I elevations were similar between healthy and HIV-infected subjects in Study 5 and between healthy and atopic dermatitis subjects in Study 6. A different troponin assay was used in these two studies compared to the other studies, and these two studies had no placebo controls. The clinical significance of these asymptomatic post-vaccination elevations of troponin-I is unknown.

Among the cardiac AESIs reported, 6 cases (0.08%) were considered to be causally related to JYNNEOS vaccination and included tachycardia, electrocardiogram T wave inversion, electrocardiogram abnormal, electrocardiogram ST segment elevation, electrocardiogram T wave abnormal, and palpitations.

None of the cardiac AESIs considered causally related to study vaccination were considered serious.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of JYNNEOS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure.

Cardiac Disorders: myocarditis, pericarditis

Immune System Disorders: hypersensitivity reactions, including angioedema, rash, and urticaria

Nervous System Disorders: dizziness, syncope

General disorders and administration site conditions: injection site warmth, injection site vesicles

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Available human data on JYNNEOS administered to pregnant women are insufficient to inform vaccine-associated risks in pregnancy.

The effect of JYNNEOS on embryo-fetal and post-natal development was evaluated in four developmental toxicity studies conducted in female rats and rabbits. In two studies, rats were administered a single human dose of JYNNEOS (0.5 mL) once prior to mating and on one or two occasions during gestation. In the third study, rats were administered a single human dose of JYNNEOS (0.5 mL) on two occasions during gestation. In the fourth study, rabbits were administered a single human dose of JYNNEOS (0.5 mL) once prior to mating and on two occasions during gestation. These animal studies revealed no evidence of harm to the fetus [see Data].

Data

Animal Data

Developmental toxicity studies were conducted in female rats and rabbits. In one study, female rabbits were administered a single human dose of JYNNEOS (0.5 mL) by the subcutaneous route on three occasions: prior to mating, and on gestation days 0 and 14. Three studies were conducted in female rats administered a single human dose of JYNNEOS (0.5 mL) by the subcutaneous route on two or three occasions: prior to mating, and on gestation days 0 and 14; or prior to mating, and on gestation day 0; or on gestation days 0 and 6. No vaccine-related fetal malformations or variations and adverse effects on female fertility or pre-weaning development were reported in these studies.

8.2 Lactation

Risk Summary

It is not known whether JYNNEOS is excreted in human milk. Data are not available to assess the effects of JYNNEOS in the breastfed infant or on milk production/excretion.

The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for JYNNEOS and any potential adverse effects on the breastfed child from JYNNEOS or from the underlying maternal condition. For preventive vaccines, the underlying condition is susceptibility to disease prevented by the vaccine.

8.4 Pediatric Use

Safety and effectiveness of JYNNEOS have not been established in individuals less than 18 years of age.

8.5 Geriatric Use

Forty-two smallpox vaccine-experienced adults 65 to 80 years of age received at least one dose of JYNNEOS (Study 4).

Clinical studies of JYNNEOS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

11 DESCRIPTION

When thawed, JYNNEOS (Smallpox and Monkeypox Vaccine, Live, Non replicating) is a milky, light yellow to pale white colored suspension for subcutaneous injection.

JYNNEOS is a live vaccine produced from the strain Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN), an attenuated, non-replicating orthopoxvirus. MVA-BN is grown in primary Chicken Embryo Fibroblast (CEF) cells suspended in a serum-free medium containing no material of direct animal origin, harvested from the CEF cells, purified and concentrated by several Tangential Flow Filtration (TFF) steps including benzonase digestion. Each 0.5 mL dose is formulated to contain 0.5 x 108 to 3.95 x 108 infectious units of MVA-BN live virus in 10 mM Tris (tromethamine), 140 mM sodium chloride at pH 7.7. Each 0.5 mL dose may contain residual amounts of host-cell DNA (≤ 20 mcg), protein (≤ 500 mcg), benzonase (≤ 0.0025 mcg), gentamicin (≤ 0.400 mcg) and ciprofloxacin (≤ 0.005 mcg).

JYNNEOS is a sterile vaccine formulated without preservatives. The vial stoppers are not made with natural rubber latex.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

JYNNEOS is an attenuated, live, non-replicating smallpox and monkeypox vaccine that elicits humoral and cellular immune responses to orthopoxviruses. Vaccinia neutralizing antibody responses in humans were evaluated to establish the effectiveness of JYNNEOS for prevention of smallpox and monkeypox.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

JYNNEOS has not been evaluated for carcinogenic or mutagenic potential, or for impairment of male fertility in animals. Developmental toxicity studies conducted in rats and rabbits vaccinated with JYNNEOS revealed no evidence of impaired female fertility [see Use in Specific Populations (8.1)].

13.2 Animal Toxicology and/or Pharmacology

The efficacy of JYNNEOS to protect cynomolgus macaques (Macaca fascicularis) against a monkeypox virus (MPXV) challenge was evaluated in several studies. Animals were administered Tris-Buffered Saline (placebo) or JYNNEOS (1 x 108 TCID50) subcutaneously on day 0 and day 28. On day 63, animals were challenged with MPXV delivered by aerosol (3 x 105 pfu), intravenous (5 x 107 pfu) or intratracheal (5 x 106 pfu) route. Across all studies, 80-100% of JYNNEOS-vaccinated animals survived compared to 0-40% of control animals.

14 CLINICAL STUDIES

14.1 Vaccine Effectiveness

Vaccine effectiveness against smallpox was inferred by comparing the immunogenicity of JYNNEOS to a licensed smallpox vaccine (ACAM2000) based on a Plaque Reduction Neutralization Test (PRNT) using the Western Reserve strain of vaccinia virus and was supported by efficacy data from animal challenge studies. [see Nonclinical Toxicology (13.2)]

Vaccine effectiveness against monkeypox was inferred from the immunogenicity of JYNNEOS in a clinical study and from efficacy data from animal challenge studies. [see Nonclinical Toxicology (13.2)]

14.2 Immunogenicity

Study 7 [7] (N=433) was a randomized, open-label study conducted at US military facilities in South Korea to compare the immunogenicity of JYNNEOS to ACAM2000 in healthy smallpox vaccine-naïve adults 18 through 42 years of age. Subjects were randomized to receive either two doses of JYNNEOS (N=220) administered 28 days apart or one dose of ACAM2000 (N=213). In the total study population, the mean age was 24 years and 23 years in subjects receiving JYNNEOS and ACAM2000, respectively; 82.3% and 86.4% of the subjects were men; 57.3% and 63.8% were white/Caucasian, 21.8% and 18.8% black/African American, 6.4% and 5.6% Asian, 3.6% and 2.8% American Indian/Alaska Native, 2.3% and 1.4% Native Hawaiian/Other Pacific, 8.6% and 7.5% other racial groups, and 24.5% and 18.8% of Hispanic/Latino ethnicity (JYNNEOS and ACAM2000, respectively).

The primary immunogenicity endpoint was geometric mean titer (GMT) of vaccinia neutralizing antibodies assessed by PRNT at “peak visits” defined as two weeks after the second dose of JYNNEOS and four weeks after the single dose of ACAM2000. Analyses of antibody responses were performed in the per-protocol immunogenicity (PPI) population, consisting of individuals who received all vaccinations and completed all visits up until the peak visit without major protocol violations pertaining to immunogenicity assessments. Table 2 presents the pre-vaccination and “peak visit” PRNT GMTs from Study 7.

PRNT GMTs were also evaluated at pre-specified time points post-vaccination and prior to the “peak visits”. The PRNT GMTs at two and four weeks after the first dose of JYNNEOS (prior to the second dose), were 23.4 (95% CI: 20.5, 26.7) and 23.5 (95% CI: 20.6, 26.9), respectively. The PRNT GMT at two weeks after the single dose of ACAM2000 was 23.7 (95% CI: 20.9, 26.8).

15 REFERENCES

1. Study 1: NCT011446372. Study 2: NCT003165243. Study 3: NCT006865824. Study 4: NCT008574935. Study 5: NCT003165896. Study 6: NCT003166027. Study 7: NCT01913353

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

• Package of 10 single-dose vials

(Package NDC number: 50632-001-03; Vial NDC number: 50632-001-01)

• Package of 20 single-dose vials

(Package NDC number: 50632-001-02; Vial NDC number: 50632-001-01)

16.2 Storage Conditions

Keep frozen at -25°C to -15°C (-13°F to +5°F).Store in the original package to protect from light.Do not re-freeze a vial once it has been thawed.Once thawed, the vaccine may be kept at +2°C to +8°C (+36°F to +46°F) for 4 weeks.Do not use the vaccine after the expiration date shown on the vial label.

17 PATIENT COUNSELING INFORMATION

•Inform vaccine recipient of the potential benefits and risks of vaccination with JYNNEOS.

•Inform vaccine recipient of the importance of completing the two dose vaccination series.

•Advise vaccine recipient to report any adverse events to their healthcare provider or to the Vaccine Adverse Event Reporting System at 1-800-822-7967 and www.vaers.hhs.gov.

Manufactured for: Bavarian Nordic A/SPhilip Heymans Alle 32900 HellerupDenmark