On October 5, 2023, the Vaccines and Related Biologic Products Advisory Committee (VRBPAC), an advisory panel to the Food and Drug Administration (FDA), voted unanimously to remove the B/Yamagata viral strain from future influenza vaccines “as soon as possible.” This change will not be effectuated overnight and, without clearer regulatory guidance, may lead to consumer and provider confusion over the appropriate flu vaccine. While VRBPAC acknowledged that flu vaccine manufacturers would need time to make this transition, FDA has begun telling them it must occur sooner.
Table 1. The Northern Hemisphere Influenza Strain Selection Process
|The World Health Organization (WHO) Global Influenza Surveillance and Response System (GISRS) reviews global data on circulating flu strains, makes a preliminary recommendation on strains to include in the next flu vaccine.||The FDA’s Vaccines and Related Biologic Products Advisory Committee (VRBPAC) reviews the WHO recommendations along with additional U.S. data, finalizes strains for U.S. vaccines.||The CDC’s Advisory Committee on Immunization Practices (ACIP), makes influenza vaccine recommendations for the U.S., including target populations.||Seasonal influenza vaccination begins in late August, early September|
|Manufacturing begins at-risk||Strains are balanced, the vaccine is filled, packed and distributed|
|WHO conducts year-round surveillance for flu viruses and sends representative viruses to WHO Collaborating Centers for Influenza, including CDC|
Each year, a well-established process depicted in Table 1 is followed to identify and select circulating influenza strains for inclusion in seasonal vaccines for the northern hemisphere, a process mirrored in the southern hemisphere. Because of the complexities associated with manufacturing influenza vaccines, candidate virus vaccines for the upcoming seasons are provided as early as possible to manufacturers who begin making vaccines at-risk, usually before regulators have made a final decision.
Currently, most influenza vaccines are quadrivalent formulations, meaning that they are manufactured to protect against four viral strains: two alphainfluenza strains and two betainfluenza strains. Of the betainfluenza strains, a particular strain called B/Yamagata, has not been detected in circulation for three years. No strain has been identified to replace the B/Yamagata strain.
For some time, VRBPAC has considered removal of the B/Yamagata strain, but the decision was not made until September of this year after the WHO influenza vaccine composition advisory committee recommended its exclusion.
How long will manufacturers have to make the switch?
Acknowledging the inevitable delay in switching from QIV to TIV, the committee voted unanimously to go ahead with inclusion of the B/Yamagata for the 2024 Southern Hemisphere QIV formulation. VRBPAC committee members agreed that the change in manufacturing required is complex and cannot occur overnight.
There is no existing scientific framework guiding the proposed removal of the B/Yamagata strain and, at the time of the VRBPAC vote on October 5, no hard deadline by which the transition to TIV was mandated.
Yet, according to company sources, FDA has met with several vaccine manufacturers in the weeks following the VRBPAC vote. During these meetings, FDA has apparently insisted that the manufacturers should be able to transition to a TIV formulation before the Northern Hemisphere’s 2024-2025 influenza season.
This differs greatly from the understating reached at the VRBPAC meeting that the transition will take more time.
Regulatory and Manufacturing Complexities
The change from four to three vaccine strains may appear simple to implement – drop a strain and continue producing vaccines – but the inherent manufacturing and regulatory complexities should not be overlooked.
Transition timelines will vary globally as, in some countries. Approximately 14 countries, including the United States, will need to update TIV licenses that preceded current QIV licenses. However, TIV formulations are not currently approved or licensed by the respective regulatory body. This may take up to 4 years to accomplish in certain jurisdictions. Moreover, some countries also rely on the FDA as their reference authority for influenza vaccine products.
There may be a period of time during which both QIV and TIV formulations of the influenza vaccine are produced and marketed. Indeed, regulatory bodies and National Immunization Technical Advisory Groups may continue to recommend both QIV and TIV until the transition is complete to reduce the possibility of supply shortages.
Payors, Providers and Patients Must Adapt
The addition of TIV to the market while QIV is still in circulation may lead to unintended consequences and will require a thoughtful transition and messaging. The co-existence of QIV and TIV formulations, even temporarily, will inevitably lead to challenges as providers and patients navigate product choices.
The inclusion of TIV may complicate an already complicated adult immunization schedule and add to vaccine fatigue. Moreover, influenza vaccine orders are typically pre-booked well in advance of the season. Should formulation changes occur subsequent to pre-booking, this may only add to confusion.
The QIV-TIV shift could disrupt patient attitudes surrounding an established vaccination regimen and patients might have concerns about reduced protection by TIV vaccine, particularly those in high-risk groups. Patients generally favor stability, particularly in healthcare. As we saw during the COVID pandemic, sudden change can complicate public health messaging and erode trust. In several ways, a the QIV-TIV transition could undermine vaccine confidence.
During the transition period, providers may spend more time consulting patients about the change and its implications. Updates to clinical guidelines will be needed to support effective counseling.
Providers will also need to manage their vaccine stock more carefully to transition from QIV to TIV and staff may need to be re-educated on the administration, storage, and efficacy differences between the two types.
The transition to a TIV framework will present other hurdles in the U.S. The American Medical Association’s CPT Editorial Panel will need to review and approve CPT codes for TIV, as it does annually for Influenza vaccines. The QIV-TIV shift adds complexity to the coding process.
The switch means that payors and group purchasers may need to revisit contracts with providers and pharmaceutical companies to include both QIV and TIV. Given that flu vaccines are typically administered without a prescription in most U.S. States, pharmacies stock of flu vaccines relies on their supply chain and contracts with manufacturers. The distribution of TIV vs. QIV may be determined on these pre-existing relationships. However, there may be a perception of inequity if some geographic locations only have access to one formulation of the vaccine.
As FDA continues to meet with manufacturers to discuss manufacturing processes, it should be mindful of the timing concerns acknowledged by its own advisory committee and a host of manufacturing, supply chain and patient considerations.
Moreover, given the manufacturing and feasibility challenges and the realistic possibility of a new quadrivalent vaccine that combines 3 alphainfluenza strains and only one betainfluenza strain, careful consideration should be given to whether this approach is better accommodated by regulatory frameworks globally. Such an approach would still eliminate the B/Yamagata strain from the QIV while greatly mitigating manufacturers complexities and the other issues raised here.