Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: Vaccines, Covid-19 vaccines, ATC code:

J07BN01
Mechanism of action

Spikevax (elasomeran) contains 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.

Clinical efficacy
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. 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.

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 (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 4.


Table 4: Vaccine efficacy analysis: confirmed COVID-19# regardless of severity starting 14 days after the 2nd dose – PPS

Spikevax                           Placebo
Incidence rate                     Incidence rate
Age group             COVID-                            COVID-                     % Vaccine Subjects           of COVID-19 Subjects               of COVID-19
(years)              19 cases                         19 cases                  efficacy (95% N                per 1,000        N                  per 1,000 n                                 n                           CI)* person-years                       person-years
Overall                                                                                  94.1 14,134      11        3.328       14,073    185          56.510
(18)                                                                              (89.3, 96.8)** 95.6
18 to <65      10,551       7        2.875       10,521    156          64.625 (90.6, 97.9)
86.4
65             3,583       4        4.595        3,552     29          33.728 (61.4, 95.2)
82.4%
 to       2,953       4        5.586        2,864     22          31.744 (48.9, 93.9)
75              630        0          0           688       7          41.968          100% (NE, 100)
#COVID-19: symptomatic COVID-19 requiring positive RT-PCR result and at least 2 systemic symptoms or 1 respiratory symptom. Cases starting 14 days after the 2 nd dose.
*Vaccine efficacy and 95% confidence interval (CI) from the stratified Cox proportional hazard model
** CI not adjusted for multiplicity. Multiplicity adjusted statistical analyses were carried out in an interim analysis based on less COVID-19 cases, not reported here.

Among 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 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 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 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 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 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 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.

Pre-boost and post-boost neutralising antibody against the B.1.617.2 (Delta) variant in adults Results of the pseudovirus neutralisation assay (PsVNA) against the B.1.617.2 (Delta) variant determined pre-booster and on Day 29 post-booster showed that administration of a booster dose of Spikevax (0.25 mL, 50 micrograms) in adults induced a 17-fold rise in neutralising antibodies against the Delta variant compared with pre-booster levels (GMFR = 17.28; 95% CI: 14.38, 20.77; n=295).

Immunogenicity in solid organ transplant recipients
The safety, reactogenicity, and immunogenicity of Spikevax (original) were evaluated in a two-part Phase 3b open-label study in adult solid organ transplant (SOT) recipients, including kidney and liver transplants (mRNA-1273-P304). A 100 microgram (0.5 mL) dose was administered, which was the dose authorised at the time of study conduct.

In Part A, 128 SOT recipients received a third dose of Spikevax (original). In Part B, 159 SOT recipients received a booster dose at least 4 months after the last dose.

Immunogenicity in the study was assessed by measurement of neutralising antibodies against pseudovirus expressing the ancestral SARS-CoV-2 (D614G) strain at 1 month after Dose 2, Dose 3, booster dose and up to 12 months from the last dose in Part A, and up to 6 months from booster dose in Part B.

Three doses of Spikevax (original) induced enhanced neutralising antibody titres compared to pre-dose 1 and post-dose 2. A higher proportion of SOT participants who had received three doses achieved seroresponse compared to participants who had received two doses. The neutralising antibody levels observed in SOT liver participants who had received three doses was comparable to the post-dose 2 responses observed in the immunocompetent, baseline SARS-CoV-2-negative adult participants. The neutralising antibody responses continued to be numerically lower post-dose 3 in SOT kidney participants compared to SOT liver participants. The neutralising levels observed one  month after Dose 3 persisted through six months with antibody levels maintained at 26-fold higher and seroresponse rate at 67% compared to baseline.

A fourth (booster) dose of Spikevax (original) enhanced neutralising antibody response in SOT participants compared to post-dose 3, regardless of the previous vaccines received [mRNA- 1273 (Moderna), BNT162b2 or any mRNA-containing combination]; however, SOT kidney participants had numerically lower neutralising antibody responses compared to SOT liver participants.

Elderly

Spikevax was assessed in individuals 18 years of age and older, including 3,768 subjects 65 years of age and older. The efficacy of Spikevax was consistent between elderly (≥65 years) and younger adult subjects (18-64 years).

Pharmacokinetic Properties

5.2. Pharmacokinetic properties

Not applicable.