BIMERVAX Injection emulsion

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 spike (S) protein of SARS-CoV-2.‍‍‍‍‍‍​​​‍​​​​​​ Following administration, an immune response is generated, both at the humoral and cellular level, against the SARS-CoV-2 RBD antigen. Neutralising antibodies against the SARS-CoV-2 RBD domain prevent the binding of RBD to the cellular target ACE2, thereby blocking membrane fusion and viral infection. In addition, BIMERVAX induces an antigen-specific T-cell immune response, which may contribute to protection against COVID-19 disease. 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 evaluated 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 a BIMERVAX booster vaccine compared with a COVID-19 mRNA vaccine (tozinameran) in adults fully vaccinated against COVID-19 with an mRNA vaccine at least 6 months before enrolment. Pregnant women, immunocompromised individuals or individuals who received immunosuppressants within 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 receiving any immunotherapy (monoclonal antibodies, plasma) prior to the study. A total of 765 subjects were vaccinated; 513 subjects received BIMERVAX and 252 subjects received the COVID-19 mRNA vaccine (tozinameran). A total of 751 subjects were analysed (504 subjects with BIMERVAX and 247 subjects with the COVID-19 mRNA 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 in 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 COVID-19 mRNA vaccine group. The immunogenicity of the BIMERVAX booster dose was based on the assessment of geometric mean titres (GMT) of neutralising antibodies measured by pseudovirion-based neutralisation assay (PBNA) against SARS-CoV-2 strain (D614G), beta, delta and omicron BA.1 variants. The GMT ratio is the result of the GMT (ID50) values of the COVID-19 mRNA vaccine (tozinameran) / BIMERVAX. Non-inferiority of BIMERVAX to the COVID-19 mRNA vaccine (tozinameran) is demonstrated if the upper bound of the 2-sided 95% confidence interval (CI) for the GMT ratio is < 1.4. Superiority of BIMERVAX to the COVID-19 mRNA vaccine (tozinameran) is demonstrated if the upper bound of the 2-sided 95% confidence interval for the GMT ratio is < 1.0 (see Table 2, GMT ratio column). Table 2: GMT ratio following the booster dose for BIMERVAX versus the COVID-19 mRNA 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 COVID-19 mRNA vaccine (tozinameran) n = 247 COVID-19 mRNA 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 evaluated in a total of 288 individuals aged 18 years and older. Individuals had previously received either a series of 2 doses of a COVID-19 mRNA vaccine (tozinameran) and one dose of BIMERVAX (cohort 1), or 3 doses of a COVID-19 mRNA 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 in both cohorts, including 11.5% of subjects aged 65 years and older. The immunogenicity of BIMERVAX as an additional booster dose was based on the assessment of geometric mean titres (GMT) of neutralising antibodies measured by pseudovirion-based neutralisation assay (PBNA) against beta, delta, omicron BA.1 and omicron BA.4/5 variants. The GMT ratio is the result of the GMT (ID50) values of the COVID-19 mRNA vaccine (tozinameran) / additional booster dose of BIMERVAX administered after 3 doses of the COVID-19 mRNA vaccine (tozinameran) or administered after 2 doses of the COVID-19 mRNA vaccine and one dose of BIMERVAX. Superiority of the additional booster dose of BIMERVAX was achieved if the upper bound 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 following an additional booster dose of BIMERVAX, administered either after a primary series with the COVID-19 mRNA vaccine and a booster dose of BIMERVAX (cohort 1), or after a primary series with the COVID-19 mRNA vaccine and a COVID-19 mRNA 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 of COVID-19 mRNA vaccine + 2 doses of BIMERVAX Cohort 2: 3 doses of COVID-19 mRNA vaccine + 1 dose of BIMERVAX GMT (95% CI) After 3rd dose n=38 GMT (95% CI) After 4th dose n=80 GMT Ratio (95% CI) GMT (95% CI) After 3rd dose n=38 GMT (95% CI) After 4th dose 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 relevant 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 COVID-19 infection. Pregnant women and immunocompromised individuals or those who received immunosuppressants within 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 receiving 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 (COVID-19 mRNA 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 COVID-19 mRNA vaccine (tozinameran) / COVID-19 mRNA 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 beta, delta and omicron BA.1 variants. GMT (geometric mean titre: ID50) data at baseline (before the booster dose) and at day 14 (2 weeks after the booster dose) 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) aged 16–17 years n = 11 Primary vaccination schedule with adenoviral vaccine (ChAdOx1-S recombinant) aged ≥ 18 years n = 40 Primary vaccination schedule with mRNA vaccine (elasomeran) aged ≥ 18 years n = 171 GMT 95% CI GMT 95% CI GMT 95% CI Before 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 relevant 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 evaluated in an ongoing multicentre phase 2b clinical study (study HIPRA-HH-3). HIPRA-HH-3 This study is an ongoing open-label, uncontrolled, multicentre, non-inferiority, single-arm phase 2b clinical study 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 immunosuppressants within the preceding 90 days could not participate in 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 the 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 study in adults (HIPRA-HH-2) at baseline and day 14 (2 weeks after the booster dose). Both groups of participants included in the analysis had no prior documented history of SARS-CoV-2 infection. Data on neutralising antibody titres against the omicron BA.1 variant at baseline (before the booster dose) and 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-eligible population) Statistic Adolescents (Aged 12–15 years) (N = 61) Adolescents (Aged 16–17 years) (N = 27) Total (Aged 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 relevant 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 the BIMERVAX vaccine. Immunocompromised population The immunogenicity and safety of a booster dose of BIMERVAX were evaluated 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 a persistent CD4 T-cell count < 400/mm³ within the last 6 months, kidney transplant recipients on maintenance immunosuppressive therapy, patients on haemodialysis/peritoneal dialysis, individuals with primary antibody deficiency on IgG replacement therapy, and individuals with autoimmune disease on rituximab/ocrelizumab therapy. The booster dose of BIMERVAX was administered at least 91 days after 3 previous doses of COVID-19 vaccine or after 2 doses plus a documented history of COVID-19 disease. Participants with a history of COVID-19 disease could be enrolled if they were diagnosed at least 91 days before 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, omicron BA.1 and BA.4/5 variants up to 12 months after the booster dose in all studied immunosuppressive conditions, except for individuals with confirmed HIV infection, in whom immunogenicity was measured by virus neutralisation assay (VNA) against the SARS-CoV-2 virus 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, a comparison with immunocompetent individuals to obtain information on the magnitude of any potential difference in immune responses was not performed. 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).