Vaccine manufacturer against Omikron
The omicron variant of SARS-CoV-2 has pushed case rates to new heights worldwide. But several manufacturers are developing vaccines adapted to the variant or have tested how well boosting it with their existing vaccines protects. However, vaccine adaptation is complicated by the fact that several subvariants of Omikron are now circulating (currently mainly BA.5 in this country) and the first Omikron subvariant, BA.1, is hardly ever seen.
The head of the EMA, Emer Cooke, expressed confidence in an interview with the Financial Times circulated Aug. 7, 2022, that her agency will be able to decide in early September whether to recommend approval for two Omicron-adapted vaccines. Subsequent approval of Covid-19 vaccines following an EMA recommendation for approval has always been a matter of days. A few weeks later, more Omicron-adapted vaccines could then be added, including those with an adaptation to the currently most common Omicron subvariants BA.4 and BA.5.
This is the latest development in a broad effort involving many companies worldwide. For example, several companies are in the process of adapting their already approved vaccines:
- BioNTech and Pfizer have been developing new versions of their mRNA vaccine since late November 2021: in addition to a monovalent Omikron BA.1 vaccine, a bivalent vaccine containing mRNA for both the Wuhan strain spike protein and that of the Omikron BA.1 variant, and also a corresponding bivalent vaccine containing an Omikron BA.4/5 component. Initial production steps and the comparative clinical trial to test efficacy and tolerability of the mono- and bivalent BA.1-adapted vaccine began back in January, according to media reports. According to a company release dated June 25, 2022, and a company presentation dated June 28, 2022, both are capable of inducing a stronger immune response against Omikron BA.1 than the original vaccine. Both also induce defense against Omikron BA.4 and BA.5, but to a lesser extent. A registration process for the bivalent vaccine with Omikron BA.1 component has been underway at the EMA since July 22, 2022 (after previous rolling review).
Positive animal experimental results are available for the bivalent vaccine adapted to BA.4/5 (see presentation, p. 78); and a Rolling Review was initiated at EMA on 09/08. Study testing will begin during August 2022.
BioNTech and Pfizer are also working on a third bivalent mRNA vaccine that is expected to achieve broader protection against different SARS-CoV-2 variants thanks to some targeted changes in the spike genes used; the starting point for this was the spikes of variant BA.2 and the Wuhan strain. A phase II trial was started with this in July 2022.
However, vaccinated persons were not without protection even with the previous vaccine: Epidemiological data showed that after three injections (basic immunization plus "booster"), it was still able to protect quite well against severe courses of infection caused by omicron variant viruses.
- Moderna began developing a vaccine adapted to Omikron at the same time as BioNTech/Pfizer and announced in February that it had begun a clinical trial. The company has been testing (in the UK) both a monovalent Omikron BA.1-adapted vaccine version and a bivalent vaccine version (Wuhan + Omikron BA.1). According to company communication dated 08/06/2022 and a company presentation to an FDA expert panel on 28/06/2022, the bivalent vaccine, when used as a booster, protects better against the Omikron variant than the company's previous vaccine, with lower protection against the BA.4 and BA.5 subvariants than against BA.1. The bivalent vaccine has been in the regulatory process with the EMA since 22/07/2022.
In addition, Moderna has a bivalent vaccine with Wuhan and Omikron BA.4/5 components in development. Study testing for this is still pending. - The protective efficacy of vaccination with the current vaccine has also been studied. According to this study, those who have only been vaccinated twice are only moderately protected, but those who have been vaccinated three times are significantly better protected.
- Novavax is developing a variant of its own vaccine adapted to Omikron BA.1; also a bivalent vaccine with Omikron BA.1 and Wuhan components. Novavax has reached Phase III with both vaccines. The company also holds out the prospect of a version of its own vaccine adapted to the BA.5 sub-variant, which will be tested in a trial starting in Q4 2022. However, according to the company's June 28, 2022, presentation, the company's EU-approved vaccine also shows high efficacy against omicron sub-variants BA.1, BA.2, and BA.5 when used as a booster vaccine (which is still being tested).
Developers of Covid-19 vaccines that are not yet licensed (or not licensed in the EU) have also responded to the Omikron variant:
- Hipra (Spain) has developed a protein-based vaccine containing as antigen a fusion protein of parts of the spike protein of the alpha and beta variants. The ongoing phase III trial is explicitly testing how well the vaccine protects against disease with the omicron variant. Results from earlier stages of development show opportunities for good protection. The vaccine is also already in rolling review with the EMA.
- Clover Biopharmaceuticals (China) is developing a protein-based bivalent vaccine containing spike protein from the Wuhan strain and Omikron. It showed efficacy against Omikron and other Variants of Concern in animal studies. The adjuvant for this vaccine is CpG 1018 from Dynavax.
- The Russian Direct Fund (RDIF), which is responsible for rolling out the Sputnik V vaccine, has reported that Sputnik V is effective against Omikron. The Moscow-based Gamaleya Institute, which developed the original version of Sputnik V, is also working on a booster version adapted to Omikron. The original version of Sputnik V is in rolling review at the EMA, which will transition to a regular approval process once all chapters of the application are submitted.
- Shionogi, a Japanese manufacturer, will ensure that its protein-based vaccine S-268019, currently in development, also provides good protection against the Omikron variant, according to the media report. To do so, it is also considering adding a component adapted to Omikron. The vaccine has reached Phase III trial testing in volunteers.
- Daiichi Sankyo - another Japanese company, but one that also has research labs in Germany - is currently investigating whether its mRNA vaccine under development can also protect against the Omikron variant, according to a media report. If not, he said, rapid adaptation to Omikron is possible. The vaccine is currently being tested in a Phase III trial with volunteers.
- Everest Medicines and Providence Therapeutics (China and Canada) have begun work on an mRNA vaccine adapted to Omikron.
- Gritstone bio (USA) is working on an Omikron-adapted variant of its Covid-19 vaccine in development based on self-amplifying mRNA (GRT-R918). It is currently being tested in a Phase I trial. The Coalition for Epidemic Preparedness Innovations (CEPI) is supporting the project.
- Phylex BioSciences (USA) is developing a bivalent mRNA vaccine to provide protection against both the delta variant and the omicron variant. The mRNA encodes the receptor binding domains of the spike proteins of both variants.
- Indian company Gennova Biopharmaceuticals is working on a variant of its mRNA vaccine adapted to Omikron. The original vaccine has reached Phase III; the Omikron version is not yet in clinical trials.
- U.S.-based Sorrento is working on an mRNA vaccine adapted from the Omikron variant. It is currently in preclinical development.
Which vaccines should they be?
Unterschiedliche Booster für die EU und die USA
On Aug. 10, 2022, research spokesman Dr. Rolf Hömke addressed this issue in a segment of the ARD program Brisant.
In July 2022, the U.S. Food and Drug Administration ( FDA) decided that it expected vaccines adapted to the Omikron BA.4 and BA.5 subvariants to be available in the U.S. in the fall of 2022 - even if this meant that these vaccines had not been tested with volunteers prior to approval. Such an approach, in which no new human testing is required after adaptation to a new viral strain, has been common for decades with influenza vaccines; but it is new for Corona vaccines.
In contrast, the European Medicines Agency ( EMA ) - according to an interview published by the Financial Times on 07/08/2022 - still plans to approve Corona vaccines only if they have also been previously tested in humans (this is in line with the results of a workshop held by various regulatory authorities on 01/07/2022). This means that booster vaccines adapted to BA.4/5 can only be licensed for the EU later than those adapted to BA.1, because study testing has not yet begun for them. For one of them, however, the rolling review has already been started so that a corresponding approval is possible as soon as possible after that for the BA.1-adapted versions.
The German Minister of Health, Karl Lauterbach, favors the use of BA.4/5-adapted vaccines.
In 5 steps to the adapted vaccine
For the development of a variant-adapted vaccine against SARS-CoV-2, starting from an already licensed vaccine, the following steps are basically foreseen by the Medicines Agency (EMA). In individual cases, however, the EMA may decide to deviate from these requirements.
1. Adaptation Of The Vaccine
The manufacturer is adapting its vaccine to the new variant in the laboratory. In the case of mRNA and vector virus vaccines, this is simply done by exchanging the RNA or DNA section that is the blueprint for the spike protein (or a piece of it) for a corresponding section for the variant spike protein.
2. Technical Quality Testing
The vaccine is subjected to technical quality testing (for concentration of ingredients, purity and stability). On the other hand, no efficacy or tolerability testing with cell cultures or animals is required.
3. Two Parallel Clinical Trials
The variant vaccine will be compared to the original vaccine in two parallel studies involving volunteers: one study as a primary vaccination, the other as a booster vaccination. It will be measured in the laboratory how reliably sufficient antibodies are produced after vaccination to render the variant virus in question harmless (neutralize it). The variant vaccine must perform better than the original one. Contact of the vaccinated with the virus is not required; no cases of disease need to be counted.
4. Testing And Approval
The manufacturer applies to the EMA for approval of the variant-adapted vaccine (called a Type II variation). The EMA may endorse it after prioritized review, and the EU Commission then approves it.
5. Production Changeover
The manufacturer and its production partners switch large-scale production in whole or in part to the variant vaccine. This is easy in the case of mRNA and vector virus vaccines, as almost nothing changes in the manufacturing process. The vaccine vials are labeled to avoid confusion with the old vaccine.
PDF download: In five stages to the variant vaccine as poster
Dr. Rolf Hömke, research spokesman for the vfa, answered questions from Radio Bremen Zwei presenter Kristin Hunfeld on December 01, 2021.
Topic: Virus variants and the efficacy of mRNA vaccines.
You can listen to the conversation here: