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Pharmacology: Pharmacodynamics: Mechanism of action: Elasomeran and elasomeran/imelasomeran both contain mRNA encapsulated in lipid nanoparticles. The mRNA encodes for the full-length SARS-CoV-2 spike protein modified with 2 proline substitutions within the heptad repeat 1 domain (S-2P) to stabilise the spike protein into a prefusion conformation. After intramuscular injection, cells at the injection site and the draining lymph nodes take up the lipid nanoparticle, effectively delivering the mRNA sequence into cells for translation into viral protein. The delivered mRNA does not enter the cellular nucleus or interact with the genome, is non-replicating, and is expressed transiently mainly by dendritic cells and subcapsular sinus macrophages. The expressed, membrane-bound spike protein of SARS-CoV-2 is then recognised by immune cells as a foreign antigen. This elicits both T-cell and B-cell responses to generate neutralising antibodies, which may contribute to protection against COVID-19. The nucleoside-modified mRNA in elasomeran/davesomeran and in andusomeran is formulated in lipid particles, which enable delivery of the nucleoside-modified mRNA into host cells to allow expression of the SARS-CoV-2 S antigen. The vaccine elicits an immune response to the S antigen, which protects against COVID-19.
Clinical efficacy: Immunogenicity in adults - after Spikevax XBB.1.5 dose (0.5 mL, 50 micrograms) versus an investigational bivalent XBB.1.5 / BA.4-5 dose (0.5 mL, 25 micrograms/25 micrograms): The safety, reactogenicity and immunogenicity of Spikevax XBB.1.5 50 micrograms and of a bivalent vaccine that contains equal mRNA amounts of Omicron XBB.1.5 and Omicron BA.4-5 spike proteins (25 micrograms XBB.1.5 / 25 micrograms BA.4-5) are evaluated in a Phase 2/3 open-label study in adults. In this study, 50 participants received Spikevax XBB.1.5 and 51 participants received the investigational bivalent XBB.1.5 / BA.4-5 (mRNA-1273- P205, Part J). The two groups were randomised 1:1.
The vaccines were administered as a fifth dose to adults who previously received a two-dose primary series of any mRNA COVID-19 vaccine, a booster dose of any mRNA COVID-19 vaccine, and a booster dose of any mRNA bivalent Original/Omicron BA.4-5 vaccine.
Spikevax XBB.1.5 and bivalent XBB.1.5 / BA.4-5 elicited potent neutralising responses at Day 15 against XBB.1.5, XBB.1.16, BA.4-5, BQ.1.1 and D614G. In the per-protocol immunogenicity set that includes all participants, with and without prior SARS-CoV-2 infection (N=49 and N=50 for Spikevax XBB.1.5 and bivalent XBB.1.5 / BA.4-5 groups, respectively), the Day 15 GMFR (95% CI) for Spikevax XBB.1.5 and bivalent XBB.1.5 / BA.4-5 was 16.7 (12.8, 21.7) and 11.6 (8.7, 15.4), respectively, against XBB.1.5 and 6.3 (4.8, 8.2) and 5.3 (3.9, 7.1) against BA.4-5.
For variants not contained in the vaccines, the Day 15 GMFR (95% CI) for Spikevax XBB.1.5 and bivalent XBB.1.5 / BA.4-5 was 11.4 (8.5, 15.4) and 9.3 (7.0, 12.3) against XBB.1.16; 5.8 (4.7, 7.3) and 6.1 (4.6, 7.9) against BQ.1.1 and 2.8 (2.2, 3.5) and 2.3 (1.9, 2.8) against D614G.
Immunogenicity in participants 18 years of age and older - after Spikevax bivalent Original/Omicron BA.4-5 booster dose (0.5 mL, 25 micrograms/25 micrograms): The safety, reactogenicity, and immunogenicity of a Spikevax bivalent Original/Omicron BA.4-5 booster dose are evaluated in an ongoing Phase 2/3 open-label study in participants 18 years of age and older (mRNA-1273-P205). In this study, 511 participants received the Spikevax bivalent Original/Omicron BA.4-5 50 microgram booster dose, and 376 participants received the Spikevax (original) 50 microgram booster dose.
Study P205 Part H evaluated the safety, reactogenicity and immunogenicity of Spikevax bivalent Original/Omicron BA.4-5 when administered as a second booster dose to adults who previously received 2 doses of Spikevax (original) (100 microgram) as a primary series and a first booster dose of Spikevax (original) (50 micrograms). In P205 Part F, study participants received Spikevax (original) (50 micrograms) as a second booster dose and the Part F group serves as a within-study, non-contemporaneous comparator group to the Spikevax bivalent Original/Omicron BA.4-5 group. In this study, the primary immunogenicity analysis was based on the primary immunogenicity set which includes participants with no evidence of SARS-CoV-2 infection at baseline (pre-booster). In the primary analysis, the observed geometric mean titre (GMT) (95% CI) at pre-booster was 87.9 (72.2, 107.1) and increased to 2 324.6 (1 921.2, 2 812.7) 28 days after the Spikevax bivalent Original/Omicron BA.4-5 booster dose. The Day 29 GMR for Spikevax Original/Omicron BA.4-5 50 microgram booster dose versus the Spikevax (original) 50 microgram booster dose was 6.29 (5.27, 7.51), meeting the pre-specified criterion for superiority (lower bound of CI >1).
The estimated neutralising antibody GMTs (95% CI) against Omicron BA.4/BA.5 adjusted for pre-booster titre and age group were 2 747.3 (2 399.2, 3 145.9) and 436.7 (389.1, 490.0) 28 days after Spikevax bivalent Original/Omicron BA.4-5 and Spikevax (original) booster doses, respectively, and the GMR (95% CI) was 6.29 (5.27, 7.51), meeting the pre-specified criterion for non-inferiority (lower bound of CI >0.667).
Immunogenicity in adults - after Spikevax bivalent Original/Omicron BA.1 booster dose (0.5 mL, 25 micrograms/25 micrograms): The safety, reactogenicity, and immunogenicity of a Spikevax bivalent Original/Omicron BA.1 booster dose are evaluated in an ongoing Phase 2/3 open-label study in participants 18 years of age and older (mRNA-1273-P205). In this study, 437 participants received the Spikevax bivalent Original/Omicron BA.1 50 microgram booster dose, and 377 participants received the Spikevax (original) 50 microgram booster dose.
Study P205 Part G evaluated the safety, reactogenicity and immunogenicity of Spikevax bivalent Original/Omicron BA.1 when administered as a second booster dose to adults who previously received 2 doses of Spikevax (original) (100 microgram) as a primary series and a booster dose of Spikevax (original) (50 micrograms) at least 3 months prior to enrolment. In P205 Part F, study participants received Spikevax (original) (50 micrograms) as a second booster dose and the Part G group serves as a within-study, non-contemporaneous comparator group to the Spikevax bivalent Original/Omicron BA.1 group.
In this study, the primary immunogenicity analysis was based on the primary immunogenicity set which includes participants with no evidence of SARS-CoV-2 infection at baseline (pre-booster). In the primary analysis, the original SARS-CoV-2 estimated neutralising antibody geometric mean titre (GMT) and corresponding 95% CI was 6 422.3 (5 990.1, 6 885.7) and 5 286.6 (4 887.1, 5 718.9) 28 days after the Spikevax bivalent Original/Omicron BA.1 and Spikevax (original) booster doses, respectively. These GMTs represent the ratio between response of Spikevax bivalent Original/Omicron BA.1 versus Spikevax (original) against the ancestral SARS-CoV-2 (D614G) strain. The GMR (97.5% CI) was 1.22 (1.08, 1.37) meeting the pre-specified criterion for non-inferiority (lower bound of 97.5% CI ≥0.67).
The estimated Day 29 neutralising antibody GMTs against Omicron, BA.1 were 2 479.9 (2 264.5, 2 715.8) and 1 421.2 (1 283.0, 1 574.4) in the Spikevax bivalent Original/Omicron BA.1 and Spikevax (original) booster groups, respectively, and the GMR (97.5% CI) was 1.75 (1.49, 2.04), which met the pre-specified superiority criterion (lower bound of CI >1).
Three-month antibody persistence of Spikevax bivalent Original/Omicron BA.1 booster vaccine against COVID-19: Participants in Study P205 Part G were sequentially enrolled to receive 50 micrograms of Spikevax (original) (n = 376) or Spikevax bivalent Original/Omicron BA.1 (n = 437) as second booster doses. In participants with no pre-booster incidence of SARS-CoV-2, Spikevax bivalent Original/Omicron BA.1 elicited Omicron-BA.1-neutralising antibody titres (observed GMT) that were significantly higher (964.4 [834.4, 1 114.7]) than those of Spikevax (original) (624.2 [533.1, 730.9]) and similar between boosters against ancestral SARS-CoV-2 at three months.
Clinical efficacy in adults: The adult study was a randomised, placebo-controlled, observer-blind Phase 3 clinical study (NCT04470427) that excluded individuals who were immunocompromised or had received immunosuppressants within 6 months, as well as participants who were pregnant, or with a known history of SARS-CoV-2 infection. Participants with stable HIV disease were not excluded. Influenza vaccines could be administered 14 days before or 14 days after any dose of Spikevax (original). Participants were also required to observe a minimum interval of 3 months after receipt of blood/plasma products or immunoglobulins prior to the study in order to receive either placebo or Spikevax (original).
A total of 30 351 subjects were followed for a median of 92 days (range: 1-122) for the development of COVID-19 disease.
The primary efficacy analysis population (referred to as the Per Protocol Set or PPS), included 28 207 subjects who received either Spikevax (original) (n=14 134) or placebo (n=14 073) and had a negative baseline SARS-CoV-2 status. The PPS study population included 47.4% female, 52.6% male, 79.5% White, 9.7% African American, 4.6% Asian, and 6.2% other. 19.7% of participants identified as Hispanic or Latino. The median age of subjects was 53 years (range 18-94). A dosing window of -7 to +14 days for administration of the second dose (scheduled at day 29) was allowed for inclusion in the PPS. 98% of vaccine recipients received the second dose 25 days to 35 days after dose 1 (corresponding to -3 to +7 days around the interval of 28 days).
COVID-19 cases were confirmed by Reverse Transcriptase Polymerase Chain Reaction (RT PCR) and by a Clinical Adjudication Committee. Vaccine efficacy overall and by key age groups are presented in Table 2. (See Table 2.)
Click on icon to see table/diagram/imageAmong all subjects in the PPS, no cases of severe COVID-19 were reported in the vaccine group compared with 30 of 185 (16%) cases reported in the placebo group. Of the 30 participants with severe disease, 9 were hospitalised, 2 of which were admitted to an intensive care unit. The majority of the remaining severe cases fulfilled only the oxygen saturation (SpO2) criterion for severe disease (≤ 93% on room air).
The vaccine efficacy of Spikevax (original) to prevent COVID-19, regardless of prior SARS-CoV-2 infection (determined by baseline serology and nasopharyngeal swab sample testing) from 14 days after Dose 2 was 93.6% (95% CI: 88.6, 96.5).
Additionally, subgroup analyses of the primary efficacy endpoint showed similar efficacy point estimates across genders, ethnic groups, and participants with medical comorbidities associated with high risk of severe COVID-19.
Immunogenicity in adults - after booster dose (0.25 mL, 50 micrograms): The safety, reactogenicity, and immunogenicity of a booster dose of Spikevax (original) are evaluated in an ongoing Phase 2, randomised, observer-blind, placebo-controlled, dose-confirmation study in participants 18 years of age and older (NCT04405076). In this study, 198 participants received two doses (0.5 mL, 100 micrograms 1 month apart) of the Spikevax (original) vaccine as primary series. In an open-label phase, 149 of those participants (Per Protocol Set) received a single booster dose (0.25 mL, 50 micrograms) at least 6 months after receiving the second dose in the primary series. A single booster dose (0.25 mL, 50 micrograms) was shown to result in a geometric mean fold rise (GMFR) of 12.99 (95% CI: 11.04, 15.29) in neutralising antibodies from pre-booster compared to 28 days after the booster dose. The GMFR in neutralising antibodies was 1.53 (95% CI: 1.32, 1.77) when compared 28 days post dose 2 (primary series) to 28 days after the booster dose.
Immunogenicity of a booster dose following primary vaccination with another authorised COVID-19 vaccine in adults: Safety and immunogenicity of a heterologous booster with Spikevax (original) were studied in an investigator-initiated study with 154 participants. The minimum time interval between primary series using a vector-based or RNA-based COVID-19 vaccine and booster injection with Spikevax (original) was 12 weeks (range: 12 weeks to 20.9 weeks). The dose used for boosting in this study was 100 micrograms. Neutralising antibody titres as measured by a pseudovirus neutralisation assay were assessed on Day 1 prior to administration and at Day 15 and Day 29 after the booster dose. A booster response was demonstrated regardless of primary vaccination.
Only short-term immunogenicity data are available; long-term protection and immunological memory are currently unknown.
Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) in the UK: COV-BOOST is a multicentre, randomised Phase 2 investigator-initiated study of third dose booster vaccination against COVID-19 with a subgroup to investigate detailed immunology. Participants were adults aged 30 years or older, in good physical health (mild to moderate well-controlled co-morbidities were permitted), who had received two doses of either Pfizer-BioNTech or Oxford-AstraZeneca (first dose in December 2020, January 2021 or February 2021), and were at least 84 days post second dose by the time of enrolment. Spikevax (original) boosted antibody and neutralising responses and was well tolerated regardless of the prime series. The dose used for boosting in this study was 100 micrograms. Neutralising antibody titres as measured by a pseudovirus neutralisation assay were assessed on Day 28 after the booster dose.
Clinical efficacy in adolescents 12 through 17 years of age: The adolescent study is an ongoing Phase 2/3 randomised, placebo-controlled, observer-blind clinical study (NCT04649151) to evaluate the safety, reactogenicity, and efficacy of Spikevax (original) in adolescents 12 to 17 years of age. Participants with a known history of SARS-CoV-2 infection were excluded from the study. A total of 3 732 participants were randomised 2:1 to receive 2 doses of Spikevax (original) or saline placebo 1 month apart.
A secondary efficacy analysis was performed in 3 181 participants who received 2 doses of either Spikevax (original) (n=2 139) or placebo (n=1 042) and had a negative baseline SARS-CoV-2 status in the Per Protocol Set. Between participants who received Spikevax (original) and those who received placebo, there were no notable differences in demographics or pre-existing medical conditions.
COVID-19 was defined as symptomatic COVID-19 requiring positive RT-PCR result and at least 2 systemic symptoms or 1 respiratory symptom. Cases starting 14 days after the second dose.
There were zero symptomatic COVID-19 cases in the Spikevax (original) group and 4 symptomatic COVID-19 cases in the placebo group.
Immunogenicity in adolescents 12 to 17 years of age - after Spikevax primary vaccination: A non-inferiority analysis evaluating SARS-CoV-2 50% neutralising titres and seroresponse rates 28 days after Dose 2 was conducted in the per-protocol immunogenicity subsets of adolescents aged 12 through 17 (n=340) in the adolescent study and in participants aged 18 through 25 (n=296) in the adult study. Subjects had no immunologic or virologic evidence of prior SARS-CoV-2 infection at baseline. The geometric mean ratio (GMR) of the neutralising antibody titres in adolescents 12 to 17 years of age compared to the 18- to 25-year-olds was 1.08 (95% CI: 0.94, 1.24). The difference in seroresponse rate was 0.2% (95% CI: -1.8, 2.4). Non-inferiority criteria (lower bound of the 95% CI for GMR > 0.67 and lower bound of the 95% CI of the seroresponse rate difference > -10%) were met.
Immunogenicity in adolescents 12 years through 17 years of age - after Spikevax (original) booster dose: The primary immunogenicity objective of the booster phase of this study was to infer efficacy of the booster dose in participants 12 years through 17 years of age by comparing post-booster immune responses (Day 29) to those obtained post-dose 2 of the primary series (Day 57) in young adults (18 to 25 years of age) in the adult study. Efficacy of the 50 microgram Spikevax booster dose is inferred if post-booster dose immune responses (nAb geometric mean concentration [GMC] and seroresponse rate [SRR]) meet prespecified noninferiority criteria (for both GMC and SRR) compared to those measured following completion of the 100 microgram Spikevax primary series among a subset of young adults (18 to 25 years) in the pivotal adult efficacy study.
In an open-label phase of this study, participants 12 years through 17 years of age received a single booster dose at least 5 months after completion of the primary series (two doses 1 month apart). The primary immunogenicity analysis population included 257 booster dose participants in this study and a random subset of 295 participants from the young adult study (ages ≥18 to ≤25 years) who previously completed a primary vaccination series of two doses 1 month apart of Spikevax. Both groups of participants included in the analysis population had no serologic or virologic evidence of SARS-CoV-2 infection prior to the first primary series dose and prior to the booster dose, respectively.
The GMR of the adolescent booster dose Day 29 GMC compared with young adults: Day 57 GMR was 5.1 (95% CI: 4.5, 5.8), meeting the noninferiority criteria (i.e., lower bound of the 95% CI >0.667 (1/1.5); point estimate ≥0.8); the SRR difference was 0.7% (95% CI: -0.8, 2.4), meeting the noninferiority criteria (lower bound of the 95% of the SRR difference >-10%).
In the 257 participants, pre-booster (booster dose-Day 1) nAb GMC was 400.4 (95% CI: 370.0, 433.4); on BD-Day 29, the GMC was 7 172.0 (95% CI: 6 610.4, 7 781.4). Post-booster booster dose-Day 29 GMC increased approximately 18-fold from pre-booster GMC, demonstrating the potency of the booster dose to adolescents. The SRR was 100 (95% CI: 98.6, 100.0).
The prespecified success criteria for the primary immunogenicity objective were met, thus enabling the inference of vaccine efficacy from the adult study.
Elderly: Spikevax (original) was assessed in individuals 6 months of age and older, including 3 768 subjects 65 years of age and older. The efficacy of Spikevax (original) was consistent between elderly (≥65 years) and younger adult subjects (18-64 years).
Pharmacokinetics: Not applicable.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity and reproductive and developmental toxicity.
General toxicity: General toxicity studies were conducted in rats (intramuscularly receiving up to 4 doses exceeding the human dose once every 2 weeks). Transient and reversible injection site oedema and erythema and transient and reversible changes in laboratory tests (including increases in eosinophils, activated partial thromboplastin time, and fibrinogen) were observed. Results suggests the toxicity potential to humans is low.
Genotoxicity/carcinogenicity: In vitro and in vivo genotoxicity studies were conducted with the novel lipid component SM-102 of the vaccine. Results suggests the genotoxicity potential to humans is very low. Carcinogenicity studies were not performed.
Reproductive toxicity: In a developmental toxicity study, 0.2 mL of a vaccine formulation containing the same quantity of mRNA (100 micrograms) and other ingredients included in a single human dose of Spikevax (original) was administered to female rats by the intramuscular route on four occasions: 28 and 14 days prior to mating, and on gestation days 1 and 13. SARS-CoV-2 antibody responses were present in maternal animals from prior to mating to the end of the study on lactation day 21 as well as in foetuses and offspring. There were no vaccine-related adverse effects on female fertility, pregnancy, embryo foetal or offspring development or postnatal development. No data are available of Spikevax (original) vaccine placental transfer or excretion in milk.
