Sunday, February 25, 2024

European Medicines Agency CHMP Approves 2 H5N1 Vaccines For Human Use


BSL-3 – Credit CDC PHIL


Despite its recent high-profile gains in both its geographic and host range, including occasional spillovers into humans, avian H5N1 has yet to acquire the ability to spread from human-to-human in a sustained or efficient manner.  

A limitation that, hopefully, will continue to prevent it from sparking a human pandemic.  

But for the better part of two decades H5Nx has been at or near the top of our pandemic worry list, and as a result a number of H5N1 pandemic vaccines have been created, tested, and sometimes stockpiled  along the way. 

The path hasn't always been easy.

Early experimental H5 (and H7) avian flu vaccines proved poorly immunogenic – requiring unusually large amounts of antigen (up to 12x normal). Adding an adjuvant - spread across two shots several weeks apart - produced a much better immune response (see 2015's JAMA: Immune Response Of H7N9 Vaccine With & Without Adjuvant).

Vaccine skepticism being what it is, how willing Americans will be to accept an adjuvanted vaccine (which have been used successfully in Europe for years), remains to be seen.  This from the CDC:

What is an adjuvant and why is it added to a vaccine?

An adjuvant is an ingredient used in some vaccines that helps create a stronger immune response in people receiving the vaccine. In other words, adjuvants help vaccines work better. Some vaccines that are made from weakened or killed germs contain naturally occurring adjuvants and help the body produce a strong protective immune response. However, most vaccines developed today include just small components of germs, such as their proteins, rather than the entire virus or bacteria. Adjuvants help the body to produce an immune response strong enough to protect the person from the disease he or she is being vaccinated against. Adjuvanted vaccines can cause more local reactions (such as redness, swelling, and pain at the injection site) and more systemic reactions (such as fever, chills and body aches) than non-adjuvanted vaccines.

Adjuvants have been used safely in vaccines for decades.
Aluminum salts, such as aluminum hydroxide, aluminum phosphate, and aluminum potassium sulfate have been used safely in vaccines for more than 70 years. Aluminum salts were initially used in the 1930s, 1940s, and 1950s with diphtheria and tetanus vaccines after it was found they strengthened the body’s immune response to these vaccines.

Newer adjuvants have been developed to target specific components of the body’s immune response, so that protection against disease is stronger and lasts longer.

In all cases, vaccines containing adjuvants are tested for safety and effectiveness in clinical trials before they are licensed for use in the United States, and these vaccines are continuously monitored by CDC and FDA once they are approved.
Additionally, we've seen problems manufacturing H5N1 vaccine in bulk (see 2019's Manufacturing Pandemic Flu Vaccines: Easier Said Than Done), particularly in egg-based production facilities.

On Friday the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorization for two H5N1 vaccine formulations (Celldemic & Incellipan), both manufactured by Seqirus in the Netherlands.

Celldemic - based on an inactivated A/turkey/Turkey/1/2005 (H5N1)-like strain with the M59C.1 adjuvant - is envisioned to be an interim early-use vaccine during the opening months of an H5N1 pandemic, until a more strain specific vaccine (Icellipan) can be produced. 

The EMA announcement on Celldemic follows, after which I'll have a bit more on H5N1 vaccine development in the United States. 



EMA has issued an opinion on this medicine
influenza vaccine (surface antigen, inactivated, prepared in cell cultures)


On 22 February 2024, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product Celldemic, intended for active immunisation against the H5N1 subtype of Influenza A virus in adults and infants from 6 months of age and above.

The applicant for this medicinal product is Seqirus Netherlands B.V..

Celldemic will be available as a 7.5 micrograms per 0.5 ml dose suspension for injection. Celldemic is an influenza vaccine (ATC code J07BB02). It contains haemagglutinin and neuraminidase surface antigens purified from inactivated A/turkey/Turkey/1/2005 (H5N1)-like strain (NIBRG 23) viruses produced in MDCK cell cultures and the adjuvant M59C.1. The Celldemic vaccine triggers an immune response against the H5N1 subtype of the influenza A virus.

The benefit of Celldemic is a robust immune response in adults and children three weeks after two doses of the vaccine given three weeks appart, as measured by haemagglutination inhibition titres against H5N1. The most common side effects in adults are pain at the injection site, fatigue, headache, malaise, myalgia and arthralgia. In children aged between 6 and 18 years, the most common side effects are injection site pain, myalgia, fatigue, malaise, headache, loss of appetite, nausea, and arthralgia. In children 6 months to less than 6 years of age, the most common side effects are tenderness at the injection site, irritability, sleepiness, change in eating habits and fever.

The full indication is:

Celldemic is indicated for active immunisation against H5N1 subtype of Influenza A virus in adults and infants from 6 months of age and above.

Celldemic should be used in accordance with official recommendations.

Detailed recommendations for the use of this product will be described in the summary of product characteristics (SmPC), which will be published in the European public assessment report (EPAR) and made available in all official European Union languages after the marketing authorisation has been granted by the European Commission.

          (Continue . . . )

The United States approved an adjuvanted monovalent H5Nx vaccine from Seqirus back in early 2020 (see FDA approval letters), and there are likely reserves of older H5Nx vaccines still in the strategic stockpile (see Vaccine: Safety & Immunogenicity Of H5N1 Vaccine Stored Up To 12 Years).

The United States government has recently entered into contracts with Seqirus to provide bulk antigen and 150 million doses (enough for 75 million people) of the vaccine within 6 months of an influenza pandemic declaration in the United States. 

Excerpts from an August 2023 Seqirus press release follow:

Under the terms of the agreement, CSL Seqirus will deliver one bulk lot of H5N8 A/Astrakhan antigen to support the U.S. government's pandemic response readiness. This is the third award CSL Seqirus has received from BARDA related to the ongoing outbreak of HPAI, following the February 2022 award to produce an H5N8 A/Astrakhan virus vaccine seed and subsequent October 2022 announcement of the selection of CSL Seqirus to deliver an H5N8 A/Astrakhan virus vaccine candidate for assessment in a Phase 2 clinical study. CSL Seqirus has been working together with BARDA in a longstanding partnership for more than a decade, which has included numerous R&D and manufacturing activities and awards in support of BARDA's pandemic preparedness objectives.

CSL Seqirus used its cell-based influenza vaccine technology, as utilized for FDA-approved AUDENZ™ (Influenza A(H5N1) Monovalent Vaccine, Adjuvanted), to manufacture the H5N8 A/Astrakhan bulk vaccine at the company's Holly Springs, North Carolina, facility, which was built in partnership with BARDA. In 2022, the Holly Springs facility successfully achieved all of BARDA's criteria required to establish domestic manufacturing capability for innovative cell-based seasonal and pandemic influenza vaccines. CSL Seqirus established and will maintain the required pandemic readiness to deliver 150 million doses of cell-based pandemic influenza vaccine within six months of an influenza pandemic declaration in the U.S.

This project has been supported in whole or in part with federal funds from the Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority (BARDA), under contract number 75A50122D00004.

Until a pandemic strain of H5Nx emerges, we won't know how effective any of these preexisting vaccines will be. But even if they prove highly effective, they are likely to be in fairly short supply during the first year of a pandemic.  

Fortunately, we have several influenza antivirals (oseltamivir, oral baloxavir, inhaled zanamivir, or intravenous peramivir) that are expected to significantly reduce morbidity and mortality from H5N1.

Whether we will have enough, and are able to get them to the people who will need it within 48 hours of falling ill (see CDC HAN #0482: Prioritizing Antiviral Treatment of Influenza in the Setting of Reduced Availability of Oseltamivir), are unknowns.

H5Nx is obviously not guaranteed to spark the next influenza pandemic, as there are plenty of other influenza A subtypes on our radar (including H1, H2, H3, H6, H7, H9 & H10 viruses).  The next pandemic may not even be an influenza virus. 

There are plenty of other candidates, including MERS-CoV, Nipah, Langya, Lassa Fever, and even Virus X - the one we don't know about yet.

For more on what the CDC and the rest of the world are doing to prepare for an H5 influenza pandemic, you may wish to visit 2023's.

How The WHO & CDC Are Developing Candidate H5N1 Vaccines