BIMERVAX Emulsion for injection

Pharmacotherapeutic group: Vaccines, COVID-19 vaccines, ATC code: J07BN04 Mechanism of action BIMERVAX is a recombinant protein vaccine whose active substance (antigen) is a fusion dimer (RBD) of the recombinant receptor-binding domain of the SARS-CoV-2 spike (S) protein.‍‍‍‍‍‍​​​‍​​​​​​ Following administration, an immune response is generated, at both humoral and cellular levels, against the SARS-CoV-2 RBD antigen. Neutralising antibodies against the SARS-CoV-2 RBD domain prevent binding of RBD to the cellular target ACE2, thereby blocking membrane fusion and viral infection. BIMERVAX additionally induces antigen-specific T-cell immune responses, which may contribute to protection against COVID-19. Clinical efficacy The efficacy of BIMERVAX was inferred by comparing immune responses (immunobridging) with an authorised COVID-19 vaccine for which vaccine efficacy had been established. Immunogenicity Individuals aged 16 years and older The immunogenicity of BIMERVAX was assessed in one pivotal multicentre phase 2b clinical trial (study HIPRA-HH-2) and in one multicentre phase 3 clinical trial (study HIPRA-HH-5). HIPRA-HH-2 Study HIPRA-HH-2 is a double-blind, randomised, active-controlled, multicentre, phase 2b non-inferiority clinical trial evaluating the immunogenicity and safety of BIMERVAX as a booster vaccine compared to an mRNA COVID-19 vaccine (tozinameran) in adults fully vaccinated against COVID-19 with an mRNA vaccine at least 6 months prior to enrolment. Pregnant women, immunocompromised individuals, or those receiving immunosuppressive therapy during the preceding 12 weeks, and individuals with prior COVID-19 infection were excluded from this phase 2b clinical trial. Participants were also required to have a minimum interval of 3 months after administration of any immunotherapy (monoclonal antibodies, plasma) prior to the study. A total of 765 subjects were vaccinated; 513 subjects received BIMERVAX and 252 subjects received an mRNA COVID-19 vaccine (tozinameran). A total of 751 subjects were analysed (504 subjects with BIMERVAX and 247 subjects with the mRNA COVID-19 vaccine) excluding subjects who tested positive for COVID-19 within 14 days of the booster dose. Randomisation was stratified by age group (18–64 versus ≥ 65 years). The median age was 42 years (range: 19 to 76 years), with similar age ranges across both vaccine arms, including 7.4% of subjects aged 65 years and older in the BIMERVAX group and 7.1% of subjects aged 65 years and older in the mRNA COVID-19 vaccine group. The immunogenicity of the BIMERVAX booster dose was based on assessment of geometric mean titres (GMT) of neutralising antibodies measured by pseudovirion-based neutralisation assay (PBNA) against the SARS-CoV-2 strain (D614G), beta, delta and omicron BA.1 variants. The GMT ratio is derived from GMT values (ID50) of the mRNA COVID-19 vaccine (tozinameran) / BIMERVAX. Non-inferiority of BIMERVAX to the mRNA COVID-19 vaccine (tozinameran) is demonstrated if the upper limit of the 2-sided 95% confidence interval (CI) for the GMT ratio is < 1.4. Superiority of BIMERVAX to the mRNA COVID-19 vaccine (tozinameran) is demonstrated if the upper limit of the 2-sided 95% confidence interval for the GMT ratio is < 1.0 (see Table 2, GMT ratio column). Table 2: GMT ratio after booster dose for BIMERVAX versus the mRNA COVID-19 vaccine (tozinameran) with neutralising antibody titres (PBNA) against SARS-CoV-2 (strain D614G), beta, delta and omicron BA.1 at 14, 28, 98 and 182 days post-booster dose (per-protocol population) BIMERVAX n = 504 mRNA COVID-19 vaccine (tozinameran) n = 247 mRNA COVID-19 vaccine (tozinameran) / BIMERVAX GMT 95% CI GMT 95% CI GMT ratio; (95% CI) Day 14 post-booster dose Strain D614G 1,949.44 1,696.03; 2,240.72 3,302.34 2,793.60; 3,903.73 1.69 (1.44; 2.00) Beta 4,268.18 3,701.04; 4,922.21 2,608.59 2,188.98; 3,108.63 0.61 (0.51; 0.73) Delta 1,459.98 1,282.22; 1,662.37 1,473.73 1,253.18; 1,733.10 1.01 (0.85; 1.20) Omicron BA.1 2,032.63 1,773.66; 2,329.40 1,209.23 1,019.34; 1,434.50 0.59 (0.50; 0.71) Day 28 post-booster dose Strain D614G 2,241.24 1,949.80; 2,576.24 2,947.35 2,494.84; 3,481.94 1.32 (1.12; 1.55) Beta 3,754.90 3,255.80; 4,330.50 2,437.02 2,046.38; 2,902.22 0.65 (0.54; 0.78) Delta 1,706.85 1,498.96; 1,943.58 1,508.08 1,283.26; 1,772.30 0.88 (0.74; 1.05) Omicron BA.1 1,516.12 1,322.89; 1,737.58 987.53 833.05; 1,170.66 0.65 (0.54; 0.78) Day 98 post-booster dose (n: BIMERVAX: 78; n: tozinameran: 42 in per-protocol subgroup) Strain D614G 1,193.17 931.14; 1,528.94 1,054.61 761.88; 1,459.83 0.88 (0.60; 1.30) Beta 1,980.37 1,526.63; 2,568.98 1,150.92 815.99; 1,623.32 0.58 (0.39; 0.88) Delta 1,981.10 1,547.00; 2,537.02 1,014.07 730.25; 1,408.20 0.51 (0.35; 0.76) Omicron BA.1 668.25 514.73; 867.56 400.71 283.27; 566.83 0.60 (0.40; 0.91) Day 182 post-booster dose Strain D614G 1,213.44 1,055.38; 1,395.17 752.09 636.46; 888.74 0.62 (0.53; 0.73) Beta 2,554.58 2,214.40; 2,947.01 1,774.54 1,489.68; 2,113.88 0.69 (0.58; 0.83) Delta 2,306.86 2,025.18; 2,627.72 1,256.46 1,068.85; 1,477.02 0.54 (0.46; 0.65) Omicron BA.1 882.67 769.93; 1,011.91 667.30 562.74; 791.28 0.76 (0.63; 0.91) n: number of participants in the per-protocol population. Abbreviations: GMT = geometric mean titres; CI: confidence interval; PBNA = pseudovirion-based neutralisation assay The immunogenicity of an additional booster dose of BIMERVAX was assessed in a total of 288 individuals aged 18 years and older. Individuals had previously received either a series of 2 doses of an mRNA COVID-19 vaccine (tozinameran) and one dose of BIMERVAX (cohort 1), or 3 doses of an mRNA COVID-19 vaccine (tozinameran) (cohort 2), and were given an additional booster dose of BIMERVAX between 6 and 12 months after the previous dose. Of these, 190 subjects were analysed in the efficacy population (80 subjects in cohort 1 and 110 subjects in cohort 2). The median age was 49 years (range: 20 to 82 years), with similar age ranges across both cohorts, including 11.5% of subjects aged 65 years and older. The immunogenicity of BIMERVAX as an additional booster dose was based on assessment of geometric mean titres (GMT) of neutralising antibodies measured by pseudovirion-based neutralisation assay (PBNA) against the beta, delta, omicron BA.1 and omicron BA.4/5 variants. The GMT ratio is derived from GMT values (ID50) of the mRNA COVID-19 vaccine (tozinameran) / additional booster dose of BIMERVAX administered after 3 doses of the mRNA COVID-19 vaccine (tozinameran) or administered after 2 doses of the mRNA COVID-19 vaccine and one dose of BIMERVAX. Superiority of the additional booster dose of BIMERVAX was achieved if the upper limit of the 2-sided 95% confidence interval (CI) for the GMT ratio was < 1 (see Table 3, GMT ratio column). Table 3: Neutralising antibody levels (PBNA) and GMT ratio after an additional booster dose of BIMERVAX, administered either after a primary series with the mRNA COVID-19 vaccine and a BIMERVAX booster dose (cohort 1), or after a primary series with the mRNA COVID-19 vaccine and an mRNA COVID-19 vaccine booster dose (cohort 2), against beta, delta, omicron BA.1 and omicron BA.4/5 at 14, 98 and 182 days post-booster dose (per-protocol population) Cohort 1: 2 doses mRNA COVID-19 vaccine + 2 doses BIMERVAX Cohort 2: 3 doses mRNA COVID-19 vaccine + 1 dose BIMERVAX GMT (95% CI) Post-dose 3 n=38 GMT (95% CI) Post-dose 4 n=80 GMT ratio (95% CI) GMT (95% CI) Post-dose 3 n=38 GMT (95% CI) Post-dose 4 n=110 GMT ratio (95% CI) Day 14 post-booster dose Beta 2,547.34 (1,741.36; 3,726.35) 5,790.20 (4,371.05; 7,670.09) 0.44 (0.28; 0.68) 2,783.85 (1,975.09; 3,923.79) 6,383.89 (5,057.19; 8,058.64) 0.44 (0.31; 0.62) Delta 1,565.21 (1,041.33; 2,352.66) 5,199.90 (3,752.82; 7,204.97) 0.30 (0.20; 0.46) 1,637.19 (1,130.5; 2,370.9) 4,085.85 (3,057.24; 5,460.52) 0.40 (0.28; 0.57) Omicron BA.1 1,528.68 (970.94; 2,406.80) 3,580.61 (2,492.90; 5,142.92) 0.43 (0.27; 0.69) 1,739.02 (1,121.56; 2,696.41) 4,049.01 (2,795.38; 5,864.84) 0.43 (0.28; 0.65) Omicron BA.4/5 1,094.55 (720.53; 1,662.72) 2,945.40 (2,216.80; 3,913.50) 0.37 (0.22; 0.62) 1,295.76 (845.10; 1,986.75) 2,506.46 (1,849.64; 3,396.52) 0.52 (0.34; 0.78) Day 98 post-booster dose Beta 1,544.65 (773.99; 3,082.64) 4,609.95 (3,474.24; 6,116.91) 0.34 (0.16; 0.69) 1,601.47 (849.42; 3,019.37) 3,743.39 (2,951.87; 4,747.14) 0.43 (0.23; 0.81) Delta 1,330.09 (672.40; 2,631.08) 1,864.55 (1,343.99; 2,586.73) 0.71 (0.36; 1.43) 1,102.65 (569.19; 2,136.06) 1,746.82 (1,305.89; 2,336.63) 0.63 (0.33; 1.22) Omicron BA.1 461.12 (214.68; 990.45) 2,110.41 (1,467.27; 3,035.45) 0.22 (0.10; 0.48) 520.63 (242.27; 1,118.79) 1,980.84 (1,371.69; 2,860.50) 0.26 (0.12; 0.56) Omicron BA.4/5 ND 1,886.95 (1,418.08; 2,510.85) ND ND 1,574.26 (1,156.85; 2,142.28) ND Day 182 post-booster dose Beta 809.61 (555.69; 1,179.56) 2,415.77 (1,814.55; 3,216.20) 0.34 (0.22; 0.52) 890.39 (633.9; 1,250.6) 2,088.80 (1,643.29; 2,655.08) 0.43 (0.30; 0.60) Delta 732.92 (489.25; 1,097.95) 1,309.33 (941.50; 1,820.86) 0.56 (0.37; 0.85) 771.85 (534.93; 1,113.71) 1,337.38 (999.37; 1,789.72) 0.58 (0.40; 0.83) Omicron BA.1 357.34 (227.83; 560.47) 1,756.94 (1,218.19; 2,533.97) 0.20 (0.13; 0.33) 404.87 (262.13; 625.33) 1,900.74 (1,315.82; 2,745.67) 0.21 (0.14; 0.32) Omicron BA.4/5 ND 1,836.26 (1,373.92; 2,454.19) ND ND 1,604.42 (1,179.06; 2,183.22) ND n: number of participants with available data for the respective endpoint Abbreviations: GMT = geometric mean titres; CI: confidence interval; ND: not determined HIPRA-HH-5 This study is an ongoing open-label, multicentre, single-arm phase 3 clinical trial evaluating the safety and immunogenicity of booster vaccination with BIMERVAX for the prevention of COVID-19 in subjects vaccinated with certain primary vaccination schedules, with or without prior non-severe COVID-19 infections. BIMERVAX was administered at least 91 days after the last dose or at least 30 days after a COVID-19 infection. Pregnant women and immunocompromised individuals or those receiving immunosuppressive therapy during the preceding 12 weeks were excluded from this phase 3 clinical trial. Participants were also required to have a minimum interval of 3 months after administration of any immunotherapy (monoclonal antibodies, plasma) prior to the study. The interim report includes data from a total of 2,646 subjects, healthy individuals (aged at least 16 years), who were vaccinated with BIMERVAX as a booster dose and had previously been vaccinated with various COVID-19 vaccines (mRNA COVID-19 vaccines: tozinameran and elasomeran, and adenoviral vaccines (COVID-19 vaccine (ChAdOx1-S [recombinant])) and COVID-19 vaccine (Ad26.COV2-S [recombinant])). Of these subjects, 230 (8%) were included in the immunogenicity population. In the immunogenicity analysis, the mRNA COVID-19 vaccine (tozinameran) / mRNA COVID-19 vaccine (tozinameran) group population comprised all subjects aged 16–17 years. Overall, the median age was 34.4 years (range: 16 to 85 years). Subjects were balanced between sexes, 52.49% male and 47.47% female. Immunogenicity was measured by pseudovirion-based neutralisation assay (PBNA) against the SARS-CoV-2 strain (D614G) and against the beta, delta and omicron BA.1 variants. GMT (geometric mean titre: ID50) data at baseline (before booster dose administration) and at day 14 (2 weeks after booster dose administration) are presented in the following table. Table 4: Geometric mean titres (GMT) of neutralising antibodies at 14 days post-booster dose of BIMERVAX in individuals aged 16 years and older – per-protocol analysis Primary vaccination schedule with mRNA vaccine (tozinameran) age 16–17 years n = 11 Primary vaccination schedule with adenoviral vaccine (ChAdOx1-S recombinant) age ≥ 18 years n = 40 Primary vaccination schedule with mRNA vaccine (elasomeran) age ≥ 18 years n = 171 GMT 95% CI GMT 95% CI GMT 95% CI Pre-booster dose Strain D614G 720.10 356.96; 1,452.64 288.58 194.56; 428.02 657.49 499.52; 865.43 Beta 471.68 208.39; 1,067.60 539.49 345.97; 841.26 497.77 376.98; 657.26 Delta 803.84 376.27; 1,717.26 283.75 182.43; 441.35 914.68 657.97; 1,271.55 Omicron BA.1 257.99 99.98; 665.71 159.34 94.02; 270.05 221.62 155.51; 315.84 Day 14 post-booster dose Strain D614G 4,753.65 2,356.45; 9,589.48 2,298.81 1,549.89; 3,409.63 4,437.27 3,371.158; 5,840.55 Beta 8,820.74 3,897.14; 19,964.72 5,009.47 3,212.53; 7,811.54 6,857.95 5,193.76; 9,055.38 Delta 7,564.79 3,541.05; 16,160.76 2,600.31 1,671.78; 4,044.56 5,811.47 4,180.44; 8,078.87 Omicron BA.1 5,757.43 2,231.25; 14,856.19 1,847.41 1,090.05; 3,131.00 4,379.81 3,073.24; 6,241.85 n: number of participants with available data for the respective endpoint Abbreviations: GMT = geometric mean titres; CI: confidence intervals Adolescents aged 12 to 17 years The immunogenicity of BIMERVAX in individuals aged 12 to 17 years was assessed in an ongoing multicentre phase 2b clinical trial (study HIPRA-HH-3). HIPRA-HH-3 This study is an ongoing open-label, uncontrolled, multicentre, non-inferiority, single-arm phase 2b clinical trial evaluating the safety and immunogenicity of booster vaccination with BIMERVAX in adolescents aged 12 to 17 years. BIMERVAX was administered at least 6 months after the last dose of the primary series. Adolescent females who were pregnant, and adolescent individuals who were immunocompromised or who had received immunosuppressive therapy during the preceding 90 days were not eligible for study HIPRA-HH-3. Participants with a known history of SARS-CoV-2 infection were excluded from the immunogenicity analysis. At the time of the interim analysis, a total of 240 adolescent participants were vaccinated with a booster dose of BIMERVAX. Of these, 88 individuals were eligible for the immunogenicity analysis. The primary immunogenicity analysis, measured by pseudovirion-based neutralisation assay (PBNA), compared geometric mean titres (GMT) of neutralising antibodies against the omicron BA.1 variant with those observed in young adult participants (aged 18 to 25 years) from the pivotal phase 2b adult trial (HIPRA-HH-2) at baseline and at day 14 (2 weeks after booster dose administration). Both groups of participants included in the analysis were without prior documented history of SARS-CoV-2 infection. Neutralising antibody titre data against the omicron BA.1 variant at baseline (pre-booster dose) and at day 14 post-vaccination are presented in the following table. Table 5: Neutralising antibody titres against the omicron BA.1 variant at 14 days post-booster dose of BIMERVAX in adolescents aged 12 to 17 years (immunogenicity-evaluable population) Statistic Adolescents (Age 12–15 years) (N = 61) Adolescents (Age 16–17 years) (N = 27) Total (Age 12–17 years) N = (88) Baseline Geometric mean 1,240.77 1,457.30 1,303.54 95% CI 894.78; 1,720.55 984.9; 2,156.3 1,016.05; 1,672.39 Day 14 Geometric mean 22,970.81 26,792.00 24,081.34 95% CI 18,033.27; 29,260.25 20,150.31; 35,622.86 19,741.36; 29,375.43 GMFR 18.51 18.38 18.47 95% CI 13.28; 25.81 13.15; 25.71 14.41; 23.69 ≥ 4-fold change from baseline, n (%) 54 (88.5) 27 (100) 81 (92) 95% CI 77.8; 95.3 87.2; 100 84.3; 96.7 n: number of participants with available data for the respective endpoint Abbreviations: GMFR = geometric mean fold rise; CI: confidence intervals Elderly population The immunogenicity of BIMERVAX was demonstrated in the elderly population (≥ 65 years), including 38 (7.4%) individuals who received BIMERVAX. Immunocompromised population The immunogenicity and safety of a booster dose of BIMERVAX was assessed in an open-label, multicentre, single-arm phase 2b/3 clinical trial (HIPRA-HH-4) in adults with pre-existing immunosuppressive conditions, including individuals with human immunodeficiency virus (HIV) infection with persistent CD4 T-cell count < 400/mm³ during the last 6 months, kidney transplant recipients on maintenance immunosuppressive therapy, those on haemodialysis/peritoneal dialysis, individuals with primary antibody deficiency on IgG replacement therapy, and those with autoimmune disease on rituximab/ocrelizumab therapy. The booster dose of BIMERVAX was administered at least 91 days after 3 previous doses of a COVID-19 vaccine or after 2 doses plus a documented history of COVID-19. Participants with a history of COVID-19 could be enrolled if diagnosed at least 91 days prior to enrolment. A total of 238 individuals were vaccinated with a booster dose of BIMERVAX and a total of 228 participants were analysed, excluding those who tested positive for COVID-19 within 14 days of the booster dose. The median age was 56 years (range: 21 to 90 years). Immunogenicity was measured by pseudovirion-based neutralisation assay (PBNA) against the SARS-CoV-2 strain (D614G) and against the beta and omicron BA.1 and BA.4/5 variants up to 12 months after the booster dose in all studied immunosuppressive conditions, except in individuals with confirmed HIV infection, in whom immunogenicity was measured by virus neutralisation assay (VNA) against the SARS-CoV-2 strain (D614G) and against omicron BA.2. The booster dose of BIMERVAX increased the humoral immune response in all immunosuppressive conditions, except in individuals with autoimmune disease on rituximab/ocrelizumab therapy. However, no comparison with immunocompetent individuals was performed to inform on the magnitude of the potential difference in immune responses. The clinical significance of the reported immune responses in immunocompromised individuals is therefore unknown. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with BIMERVAX in one or more subsets of the paediatric population in the prevention of COVID-19 (see section 4.2 for information on paediatric use).