A candidate vaccine virus (CVV) is an influenza (flu) virus that has been prepared by CDC or another public health partner that can be used by vaccine manufacturers to produce a flu vaccine. In addition to preparing CVVs for seasonal flu vaccine production, CDC routinely develops CVVs for novel avian influenza (bird flu) viruses with pandemic potential as part of pandemic preparedness activities. Some novel bird flu viruses with pandemic potential are “highly pathogenic avian influenza” (HPAI) viruses, which means they are deadly to domestic poultry, including chickens. Data collected through global and animal flu surveillance informs the selection of CVVs, and experts choose CVVs against bird flu viruses in nature (“wild type” viruses) that pose a risk to human health.
The creation of a CVV for a novel bird flu virus is a multistep process that takes months, from start to finish. Creating a bird flu CVV is usually more complicated than the process for creating a seasonal flu CVV. There are five steps involved in the creation of a bird flu CVV, including the following:
Request for CVV Exclusion from the USDA Select Agents List
Next, a request is filed with the USDA to get the CVV excluded from the “Select Agent” list. Certain biological agents or toxins that pose a potential severe threat to public health and safety are designated as “Select Agents.” (For more information on select agents, see the Federal Select Agent Program website.) Highly pathogenic bird flu viruses are Select Agents, and so a CVV made from one of these viruses is treated as a Select Agent until an exclusion is granted by USDA. This is necessary before the CVV can be given to flu vaccine manufacturers. To obtain USDA Select Agent exclusion, CDC prepares and submits appropriate documentation to USDA, including all of the virus attenuation verification data. USDA then reviews the application and decides whether the CVV can be excluded as a Select Agent.
Jen covers global health stories, covering everything from malnourishment to malaria. A portion of the health She had previously worked as a freelancer in Myanmar and the Czech Republic, as well as at the UK’s Channel 4 News and the newspaper Telegraph.
Production of the candidate vaccine virus (CVV)
The first step in developing a CVV against a specific bird flu virus is to identify the wild type bird flu virus that is posing or may pose a risk to human health. Flu vaccines protect against specific flu viruses.
A CVV must possess two characteristics. Firstly, it must be able to initiate an immune response that protects against the wild type bird flu virus. Second, the CVV must grow well in eggs. The majority of flu shots available today are made with egg-based technology, which necessitates the growth of the CVV in chicken eggs, meaning that the CVV must develop successfully in chicken eggs. (To learn more about the manufacturing process of vaccines, refer to “How Influenza (Flu) Vaccines Are Made.” Highly pathogenic bird flu viruses are extremely difficult to grow in eggs because they destroy chicken eggs and cause serious illness and death in birds. Furthermore, in animal models of human disease, HPAI viruses result in serious illness and even death. Because they won’t grow in eggs and may be harmful to humans, the wild type viruses found in nature cannot be used to create the CVV. CDC researchers employ “reverse genetics” to produce an attenuated (i e. , milder or weakened) strain of the bird flu virus that will both grow well in chicken eggs and not cause serious illness in birds, protecting agricultural interests (so that vaccine manufacturers can use it to produce vaccine)
The neuraminidase (NA) and a modified hemagglutinin (HA) gene from the bird flu virus are combined with six genes from a commonly used human flu virus that grows well in chicken eggs by CDC scientists using reverse genetics. If available, viral RNA from the wild type virus is used to create the HA and NA from the bird flu virus. If not, synthetic methods are employed. The “polybasic cleavage site,” which is where the virus kills birds and chicken eggs, is removed from the HA in order to alter it. The prepared DNA is inserted into cells, which are usually “Vero” cells in the lab, and given three days to grow. Subsequently, it is extracted from the cells and introduced into eggs to cultivate viral stocks. Testing is done on the virus stocks to see if there is enough virus in the eggs, and the CVV is examined to see if it meets the regulatory requirements needed to be developed into a vaccine.
The FDA’s “good laboratory practice” (GLP) guidelines for biologics intended for human use must be followed when creating a CVV. GLP is a quality system that addresses the organizational structure and the circumstances in which the development of vaccines is organized, carried out, tracked, documented, stored, and reported in accordance with FDA regulations.
The attenuated virus that emerges from this procedure should ideally be “like” the wild-type bird flu virus in terms of antigens. This virus should thrive in chicken eggs and trigger the intended immune response.
After reverse genetics is used to create the CVV and it is cultivated in eggs, e. , saved), the CVV goes through several tests as part of the quality evaluation process. These steps are listed and described below.
- Experts in gene sequencing verification confirm that the generated CVV is genetically stable and free of unforeseen alterations or mutations. In order to make sure the CVV is as similar to the wild type bird flu virus it is meant to protect against as possible, PCR and whole genome sequencing are employed.
- Experts in Impurity Testing Flu ensure that the CVV is free of bacteria and fungi.
- Exclusivity Testing: The CVV is examined to make sure it contains only the virus that was meant to be there and hasn’t been tampered with.
- Testing for Trypsin-Dependent Plaque Assays: This laboratory procedure verifies that the polybasic cleavage site (i.e., e. the portion of the virus that causes death in chickens and chicken eggs) has been eliminated.
- Testing for Embryo Lethality This test verifies that the CVV does not cause the death of chicken embryos. This is a required for egg-based vaccine production.
- Antigenic Characterization: To determine whether the CVV is antigenically similar to the bird flu virus that it is meant to protect against, the CDC uses the hemagglutinin inhibition (HI) test. Because of this antigenic similarity, antibodies generated in response to the CVV will also be able to identify and specifically target the corresponding wild-type bird flu virus.
The CVV undergoes a battery of animal tests after quality assurance tests to verify that the resulting virus stock is attenuated (i.e., e. , made milder or weakened). Determination of attenuation requires testing in chickens and ferrets. Specific steps are described below:
- Testing for Pathogenicity in Chickens: After receiving a CVV vaccination, chickens are monitored to ensure they do not become ill or die. This examination confirms that in domestic poultry, the CVV is not highly pathogenic. This indicates that the use of the CVV during egg-based production can be done so without endangering agricultural interests. An outside partner, like the Southeastern Poultry Research Laboratory (SEPRL) of the United States Department of Agriculture (USDA), conducts pathogenicity testing on chickens. The results of this testing are then shared with CDC.
- Testing for pathogenicity in ferrets In order to make sure the CVV does not cause serious illness, ferrets are also vaccinated and monitored. Ferrets are frequently used as a model to infer flu disease and transmission characteristics in humans because flu viruses infect and cause disease in them similarly to humans.
This is the last stage in making sure the CVV has been appropriately attenuated and is safe for mammals and birds.
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