BIMERVAX (Bimervax)

What Is BIMERVAX and What Is It Used For?

BIMERVAX (also known by its development code PHH-1V) is a COVID-19 vaccine manufactured by HIPRA Human Health S.L., a Spanish pharmaceutical company. Unlike mRNA-based COVID-19 vaccines such as those developed by Pfizer-BioNTech and Moderna, BIMERVAX uses a protein subunit approach — a well-established vaccine technology that has been used for decades in other vaccines, including those for hepatitis B and pertussis.

The vaccine contains a recombinant fusion protein consisting of the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, presented as a homodimer. This protein is produced using recombinant DNA technology in Chinese Hamster Ovary (CHO) cells, a standard system widely used in biopharmaceutical manufacturing. The RBD is the critical part of the spike protein that the virus uses to bind to human ACE2 receptors and enter cells, making it a prime target for neutralizing antibodies.

To enhance the immune response, the RBD protein is combined with SQBA, an oil-in-water squalene-based adjuvant. Adjuvants are substances that boost the body's immune response to a vaccine antigen, allowing for a stronger and more durable protective response. Squalene-based adjuvants have an extensive safety record, having been used in seasonal influenza vaccines administered to hundreds of millions of people worldwide.

BIMERVAX received EU marketing authorisation from the European Commission on 30 March 2023, initially as a booster dose for individuals aged 16 years and older who had previously received an mRNA COVID-19 vaccine. In October 2023, it became the first COVID-19 vaccine to receive WHO prequalification under the organisation's updated evaluation process, a significant milestone for global vaccine access. The vaccine has also been approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for individuals aged 12 years and older.

Subsequently, adapted versions of BIMERVAX have been developed to target emerging SARS-CoV-2 variants. The BIMERVAX XBB.1.16 formulation (containing the active substance damlecovatein) received EU marketing authorisation in October 2024, and the BIMERVAX LP.8.1 formulation has also been authorised. These updated versions can be administered regardless of previous COVID-19 vaccination history, broadening the vaccine's utility as the pandemic evolves.

Mechanism of Action

When BIMERVAX is injected intramuscularly, the recombinant RBD fusion protein is recognised by the immune system as a foreign antigen. Antigen-presenting cells process the protein and present it to T lymphocytes and B lymphocytes, triggering both humoral (antibody-mediated) and cellular immune responses. The resulting neutralizing antibodies target the RBD of the spike protein, blocking the virus from binding to ACE2 receptors on human cells. This immunological memory allows the body to mount a rapid and effective response upon subsequent exposure to SARS-CoV-2.

The SQBA adjuvant enhances this process by creating a local immunostimulatory environment at the injection site, recruiting immune cells and promoting antigen uptake. Clinical trials have demonstrated that BIMERVAX induces robust neutralizing antibody responses against multiple SARS-CoV-2 variants, including Omicron sublineages, with immunogenicity that is non-inferior to comparator mRNA vaccines when used as a booster.

What Should You Know Before Taking BIMERVAX?

Contraindications

The primary contraindication for BIMERVAX is hypersensitivity to the active substance (the recombinant RBD fusion protein) or to any of the excipients listed in the composition. Individuals who have experienced a severe allergic reaction to a previous dose of BIMERVAX should not receive additional doses. The vaccine contains polysorbate 80 (1.18 mg per dose), which may cause allergic reactions in sensitive individuals. Healthcare professionals should be aware that patients with known polysorbate allergies may need to be assessed before vaccination.

As with any injectable vaccine, BIMERVAX should be administered with caution in individuals with thrombocytopenia or any coagulation disorder, as bleeding may occur following intramuscular injection. In such cases, firm pressure should be applied to the injection site for at least two minutes without rubbing.

Warnings and Precautions

Events of anaphylaxis have been reported with COVID-19 vaccines as a class. Appropriate medical treatment and supervision must always be readily available when administering BIMERVAX. Recipients should be observed for at least 15 minutes after vaccination for any signs of an allergic reaction. If an anaphylactic reaction occurs, standard emergency treatment should be instituted immediately, and the event reported to the relevant pharmacovigilance authorities.

During clinical studies of BIMERVAX, one case of pericarditis (inflammation of the membrane surrounding the heart) was observed. While myocarditis and pericarditis have been associated with mRNA COVID-19 vaccines, particularly in younger males, this remains a theoretical concern for all COVID-19 vaccines. Recipients should be advised to seek immediate medical attention if they develop symptoms suggestive of myocarditis or pericarditis, such as persistent chest pain, shortness of breath, or palpitations after vaccination.

BIMERVAX is designated as being under additional monitoring by the European Medicines Agency, as indicated by the black inverted triangle symbol. This allows for rapid identification of any new safety information. Healthcare professionals are encouraged to report any suspected adverse reactions through their national reporting systems.

Vaccination with BIMERVAX may not protect all recipients. As with all vaccines, no vaccine is 100% effective, and breakthrough infections can occur. Vaccinated individuals should continue to follow public health recommendations, including any local guidelines regarding additional protective measures during periods of high transmission.

Pregnancy and Breastfeeding

There is limited clinical experience with the use of BIMERVAX during pregnancy. Animal reproductive toxicity studies conducted in rats did not indicate any direct or indirect harmful effects on pregnancy, embryo-foetal development, parturition, or postnatal development. Rats received a vaccine dose equivalent to a full human dose at multiple time points before mating and during gestation, with no adverse effects observed.

However, as a precautionary measure, BIMERVAX should only be used during pregnancy when the potential benefits justify the potential risks to the mother and foetus. This is consistent with general recommendations for vaccination during pregnancy, where clinical data may be limited but the risk of the disease itself may be significant.

It is unknown whether BIMERVAX or its components are excreted in human breast milk. Given the negligible systemic exposure expected following intramuscular injection of a protein subunit vaccine, a risk to breastfed newborns or infants cannot be excluded but is considered unlikely. The decision to vaccinate during breastfeeding should take into account both the potential benefit to the mother and any theoretical risk to the infant.

Animal studies showed no vaccine-related adverse effects on fertility. No clinical fertility studies have been conducted in humans, but there is no biological mechanism by which a protein subunit vaccine would be expected to affect fertility.

How Does BIMERVAX Interact with Other Drugs?

To date, no formal drug interaction studies have been performed with BIMERVAX. This is consistent with the regulatory approach for most COVID-19 vaccines, where the urgency of deployment has meant that comprehensive interaction studies are conducted post-authorisation. However, based on the pharmacological properties of the vaccine and the general principles of vaccinology, several important considerations apply.

BIMERVAX should not be mixed in the same syringe with any other vaccines or medicinal products. If BIMERVAX is to be given at the same time as another injectable vaccine, the vaccines should always be administered at different injection sites, preferably in different limbs. The concomitant administration of BIMERVAX with other vaccines (such as influenza vaccines) has not been specifically studied in clinical trials, although general guidance from public health authorities typically permits co-administration of COVID-19 vaccines with other routine vaccines.

Immunosuppressive Therapies

Individuals receiving immunosuppressive therapies, including high-dose systemic corticosteroids, biological disease-modifying antirheumatic drugs (bDMARDs), organ transplant recipients on anti-rejection medications, and patients undergoing chemotherapy, may have a diminished immune response to BIMERVAX. The degree of immune suppression depends on the specific agent, dose, and timing relative to vaccination.

For patients on immunosuppressive therapy, vaccination should ideally be timed to coincide with periods of lowest immunosuppression, when possible. However, the potential benefit of vaccination in these high-risk populations generally outweighs the risk of a suboptimal response, and vaccination should not be withheld solely because of immunosuppressive therapy. Specialist advice should be sought when scheduling vaccination for patients on complex immunosuppressive regimens.

Concomitant Vaccination

While co-administration of BIMERVAX with influenza vaccines or other routine immunisations has not been formally studied, the WHO and many national immunisation technical advisory groups (NITAGs) generally recommend that COVID-19 vaccines may be given simultaneously with other vaccines. When co-administration is performed, different injection sites should be used and any adverse events should be recorded separately for each vaccine. Patients should be informed that they may experience a higher overall rate of local or systemic reactions when receiving multiple vaccines simultaneously.

What Is the Correct Dosage of BIMERVAX?

BIMERVAX is supplied as a multidose vial containing 5 mL of emulsion for injection, providing 10 doses of 0.5 mL each. The vaccine must be administered by a healthcare professional trained in the recognition and management of anaphylaxis. Before administration, the vial should be gently swirled (not shaken) and visually inspected for particulate matter and discolouration. The vaccine is an opaque, whitish emulsion that should be discarded if it appears otherwise.

Adults (18 years and older)

Adolescents (12–17 years)

Children (under 12 years)

Elderly

Renal and Hepatic Impairment

Missed Dose

As BIMERVAX is typically administered as a single dose (particularly the adapted versions), missed doses are less of a concern compared to multi-dose vaccine regimens. If a planned booster dose is delayed, it should be administered as soon as possible. There is no need to restart the vaccination schedule. The immune system retains immunological memory, and a delayed booster dose is expected to still provide benefit.

Overdose

There is limited data on overdose with BIMERVAX. In the event that a dose larger than 0.5 mL is inadvertently administered, the individual should be monitored for any adverse reactions. Supportive care should be provided as needed. Given the nature of the vaccine components (a protein antigen and adjuvant), overdose is unlikely to produce effects qualitatively different from those seen at the recommended dose, although local and systemic reactions may be more pronounced. Any suspected overdose should be reported to the relevant pharmacovigilance authority.

What Are the Side Effects of BIMERVAX?

Like all medicines and vaccines, BIMERVAX can cause side effects, although not everybody gets them. The safety profile of BIMERVAX has been evaluated in clinical trials involving thousands of participants. The vast majority of reported adverse reactions were mild to moderate in intensity and resolved spontaneously within one to three days after vaccination, without requiring medical intervention.

The safety data presented below are based on the pivotal Phase III clinical trial (HIPRA-HH-2) and post-marketing surveillance data. Adverse reactions are classified according to their frequency using the standard MedDRA convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), and rare (≥1/10,000 to <1/1,000).

Serious Adverse Events

Serious adverse events associated with BIMERVAX are very rare. During clinical studies, one case of pericarditis was observed. Myocarditis and pericarditis have been identified as very rare risks associated with COVID-19 vaccines as a class, particularly mRNA vaccines. While the incidence with BIMERVAX appears to be extremely low, recipients should be advised to seek immediate medical attention if they experience new-onset chest pain, shortness of breath, or palpitations in the days following vaccination.

As with all vaccines, anaphylaxis is a theoretical risk. Events of anaphylaxis have been reported with COVID-19 vaccines, and vaccination should therefore be carried out in settings where emergency treatment for anaphylaxis is available. The risk is estimated at approximately 1 per million doses for COVID-19 vaccines as a class.

Side Effects in Adolescents

The safety profile of BIMERVAX in adolescents (aged 12–17 years) is generally similar to that observed in adults. However, malaise (feeling generally unwell) was reported more frequently in the adolescent population. As with adults, the majority of adverse reactions were mild to moderate and self-limiting. Parents and caregivers should monitor adolescent vaccine recipients and contact a healthcare provider if symptoms persist beyond 72 hours or if any serious symptoms develop.

How Should You Store BIMERVAX?

One of the practical advantages of BIMERVAX over some other COVID-19 vaccines is its straightforward storage requirements. The vaccine is stored at standard refrigerator temperatures, eliminating the need for ultra-cold freezers or complex cold chain logistics that have challenged the distribution of mRNA-based COVID-19 vaccines, particularly in low- and middle-income countries.

• Storage temperature: 2°C to 8°C (standard pharmaceutical refrigerator)
• Do not freeze: The vaccine must not be frozen at any point. If the vaccine has been accidentally frozen, it must be discarded
• Light protection: Store in the outer packaging to protect from light
• Shelf life (unopened): 21 months when stored at 2–8°C
• After first puncture: The multidose vial must be used within 6 hours and kept at 2–8°C during this period
• Do not use after the expiry date stated on the carton and vial label

For healthcare facilities and vaccination centres, the vaccine should be stored in a validated pharmaceutical refrigerator with continuous temperature monitoring. Temperature excursions outside the 2–8°C range should be documented and the vaccine assessed for usability according to the manufacturer's stability data before administration. The World Health Organization recommends that all vaccines be stored in purpose-designed vaccine refrigerators that maintain temperatures within the recommended range.

The 21-month shelf life at standard refrigerator temperatures is particularly advantageous for global distribution and stockpiling purposes, and was a key factor in the vaccine receiving WHO prequalification. This stability profile reduces vaccine wastage and facilitates deployment in regions with limited cold chain infrastructure.

What Does BIMERVAX Contain?

Active Substance

The active substance in BIMERVAX is a recombinant SARS-CoV-2 spike (S) protein receptor binding domain (RBD) fusion dimer, produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology. Each 0.5 mL dose contains 40 micrograms of this protein. The original formulation (selvacovatein) targets the Alpha (B.1.1.7) and Beta (B.1.351) variant RBDs, while the adapted version BIMERVAX XBB.1.16 (damlecovatein) targets the Omicron XBB.1.16 subvariant, and the BIMERVAX LP.8.1 version targets the Omicron LP.8.1 subvariant.

Adjuvant (SQBA)

The SQBA adjuvant is an oil-in-water emulsion containing the following components per 0.5 mL dose:

• Squalene: 9.75 mg — a naturally occurring lipid found in plants, animals, and humans, used to create the oil-in-water emulsion
• Polysorbate 80: 1.18 mg — an emulsifier that stabilises the adjuvant emulsion (note: may cause allergic reactions in sensitive individuals)
• Sorbitan trioleate: 1.18 mg — a surfactant that helps maintain the emulsion stability
• Sodium citrate: 0.66 mg — a buffer component
• Citric acid: 0.04 mg — a pH adjustment agent
• Water for injections

Other Excipients

The buffer solution contains the following excipients:

• Disodium phosphate dodecahydrate
• Potassium dihydrogen phosphate
• Sodium chloride
• Potassium chloride
• Water for injections

The vaccine does not contain any preservatives, antibiotics, human-derived or animal-derived materials (other than CHO cell-derived protein), latex (in the vial stopper), or adjuvants containing aluminium salts. The squalene used in the SQBA adjuvant is of synthetic origin. The vaccine does not contain any live virus, inactivated virus, or genetic material (mRNA or DNA).