Delivery of Care

Achoo: the flu season reveals gaps in public protection

Flu vaccines exist, such as Flublok, a recombinant vaccine with clinical evidence supporting its effectiveness for people 50 years and older, but consumers, insurers, pharmacies and primary care providers remain largely “unaware” of its availability

Image courtesy of the R.I. Department of Health

The highest number of hospitalizations because of influenza occurred for Rhode Island residents older than 50 years of age during the week of Feb. 4-10, 2018.

By Richard Asinof
Posted 2/19/18
As the flu season continues to wreak havoc in Rhode Island and across the nation, the availability of a potentially more effective vaccine such as Flublok, an FDA-approved recombinant vaccine, remains a stealth health policy tale. Whether or not Flublok will be included in purchases for next year’s flu vaccine by Rhode island will be decided in an April meeting of the R.I. Department of Health’s Vaccine Advisory Committee.
Why hasn’t Sanofi Pasteur, the new owner of Protein Sciences, which manufactures Flublok, used the opportunity presented the lack of vaccine efficacy in the current flu vaccine, to redouble its efforts to market Flublok? If the Vaccine Advisory Committee recommends buying Flublok for Rhode Island’s flu vaccine supply, should it also consider a public education campaign to accompany that decision? Given the lower immune response often found in seniors, and the high number of seniors who in turn have been hospitalized during the current flu season, wouldn’t it make sense to offer a more effective vaccine to people 50 years and older, even if it may cost a bit more than the other vaccines?
What would happen if CVS, or, for that matter, Blue Cross & Blue Shield of Rhode Island, made a decision to offer Flublok to its customers and members who are 50 years and older, as a way to prevent complications from the flu season? Could it be turned into a public relations success story, the kind of win-win situation where health care leaders in Rhode Island are putting public health over profits? And, wouldn’t it save on medical costs in the long run?
That kind of conversation has been sadly missing from the news coverage about the widespread flu season this year by most of the news media in Rhode Island.

PROVIDENCE – The coughing, wheezing and sneezing of a bad flu season is upon us in full force, causing emergency rooms to overflow and hospital beds to fill up with sick patients.

And, with the severity of this year’s flu season has come questions about the effectiveness of the current flu vaccine manufactured using egg-based technology, in particular, concerns about whether the drift of the flu virus during the manufacturing process of the vaccine translated into less effective protection against the predominant flu virus strain in circulation, H3N2.

Recent analyses have estimated that the flu shot manufactured through egg-based technology is only 25 percent effective against the H3N2 flu strains circulating this season, according to the Centers for Disease Control and Prevention.

In turn, the public messaging about the lack of effectiveness about the flu vaccine may have contributed to some consumers deciding not to get a flu shot this year, which many public health practitioners have warned is a poor choice.

The untold story, however, is this: why has information about potentially more effective flu shots, particularly for people over 50 years of age, remained a stealth public health tale?

As Helen Branswell of STAT reported in her Feb. 6 story, “Some flu vaccines may work better than others – but guidance to the public is scant,” “Last fall some people in the know about influenza science got picky when it came time to get their flu shots.”

Branswell continued: “They didn’t want to roll up their sleeve for any old vaccine [offered] at their doctor’s office or workplace clinic.” Instead, those in the know sought out specific products, including Flublok, an FDA-approved vaccine made through recombinant technology and not from egg-based technology.

While the Centers for Disease Control and Prevention does not offer any recommendations about the different technologies employed to make flu vaccines, the pricing policies for flu shots and public health bulk-buying programs for flu shots tend to make for a kind of de facto public health policy decision-making.

The most recent flu data from the R.I. Department of Health underscored the potential consequences of the missed opportunities to provide better protection from a flu shot with greater efficacy against the H3N2 flu, particularly for people 50 years and older.

For the week of Feb. 4-10, 2018, the agency reported in its weekly influenza update that the geographic spread of flu was “widespread” and the intensity level was “high.” Influenza-like illness represented 8.4 percent of all patient visits to providers, more than double the number for past flu seasons between 2014 and 2018. Hospital influenza tests revealed that 645 of the 778 flu strains identified were for were the H3N2 strain or the A strain [not subtyped]. Approximately three-quarters of 140 patients admitted to hospitals in Rhode Island diagnosed with flu were 50 years of age or older.

As Marvel’s Stan Lee often had his characters say, “Nuf said?”

Securing a broader market distribution channel
As regular readers of ConvergenceRI may recall, Flublok, manufactured by Protein Sciences in Meriden, Conn., has struggled to secure and maintain a distribution channel for its FDA-approved recombinant vaccine, given the increasing market consolidation of big pharmacy chains, despite clinical evidence in a study published in 2017 by the New England Journal of Medicine that found Protein Sciences’ recombinant flu vaccine “provided better protection” than standard flu vaccines among older adults.

Many big box stores and pharmacies use the lure of convenience of flu shots to bring customers into their retail outlets. In turn, those large market chains often choose to purchase the lowest-priced flu vaccine rather than the most-effective vaccine, putting profits ahead of public health, as is their right.

As ConvergenceRI reported: “Flublok, which Protein Sciences calls the world’s first licensed influenza vaccine that is manufactured using recombinant DNA technology, is approved for use for anyone over 18 years of age. It is marketed as being a highly pure product: it contains no egg protein, gelatin, thimersal [a mercury derivative], latex, gluten, antibiotics, formaldehyde or influenza virus, according to Protein Sciences.”

In addition, ConvergenceRI reported: “Unlike the traditional 70-year-old egg-based technology that is used to produce most flu vaccines, Protein Sciences uses recombinant technology to produce large quantities of the protein that is the active ingredient in flu vaccines.”

Further, ConvergenceRI reported: “A recent clinical study of Flubok involving approximately 9,000 adults 50 years or older showed that Flublok recipients were 31 percent less likely to develop laboratory-confirmed influenza than people who received a traditional, egg-based vaccine.”

[See links below to ConvergenceRI stories, “Flublok, the first recombinant flu vaccine, [promises to] reshape the market,” and “Show me the vial.”]

Buy out by Sanofi
On July 11, 2017, Protein Sciences was purchased by global biotech giant Sanofi Pasteur for approximately $750 million. The hope at the time was that the acquisition would provide the marketing expertise and financial oomph to propel Flublok to capture a larger share of the flu vaccine. [See link below to ConvergenceRI story, “Sanofi acquires Protein Sciences in $750 million deal.”]

“The acquisition of Protein Sciences will allow us to broaden our flu portfolio with the addition of a non-egg based vaccine,” said David Loew, Sanofi executive vice president and head of Sanofi Pasteur's vaccines division, in the news release announcing the acquisition.

In November of 2017, as worries about the efficacy of the egg-based flu vaccine first surfaced, because of alleged “drift” of the vaccine’s capability to protect against H3N2 flu virus, the strain of the virus that was in circulation, little was heard from Sanofi in marketing Flublok and its recombinant vaccine, which offered far greater protection than the single flu shot being offered by most clinics and big box stores, given the emerging market opportunity.

“Our experiments suggest that influenza virus antigens grown in systems other than eggs are more likely to elicit protective antibody responses against H3N2 viruses that are currently circulating,” said Scott Hensley, Ph.D., associate professor of microbiology in the Perelman School of Medicine at the University of Pennsylvania, in a press release, as reported in Healio Infectious Disease News on Nov. 8, under the headline, “H3N2 mutation responsible for reducing vaccine efficacy.”

Hensley warned at that time: “The 2017 vaccine that people are getting now has the same H3N2 strain as the 2016 vaccine, so this could be another difficult year if this season is dominated by H3N2 viruses again.”

In a study conducted by Hensley, Flublok proved to be more effective than egg-based vaccines. “Current H3N2 viruses do not grow well in chicken eggs, and it is impossible to grow these viruses in eggs without adaptive mutations,” Hensley said in a news release about the study.

In his study, Hensley and his colleagues tested serum isolated from study participants, aged 18 to 49, before and after vaccination with egg-based vaccines Fluzone and Flucelvax [a cell-based vaccine] and the non-egg vaccine, Flublok, during the 2016-2017 flu season. Among the findings was that antibody reactivity against H3N2 flu in participants increased about fourfold after vaccination with Flublok, but only minimal increases were found in antibody activity in participants who received Fluzone or Flucelvax.

Editor's note: Hensley predicted, as reported by CIDRAP News on Feb. 24, that the egg-adapted H3N2 strain problem will persist next year, because the new egg-grown H3N2 vaccine virus has the same critical T160K egg mutation that is in this season's vaccine strain.

“The only solution is not to use eggs for H3N2 vaccine production,” he said. “What we really need is a large-scale effectiveness study that compares egg-based and cell-based vaccines.”

Buy to kill?
In December of 2017, Manon Cox, the former president and CEO at Protein Sciences, was apparently forced to leave her position at the company she helped to found.

While there is absolutely no existing evidence to suggest so, a number of infectious disease researchers who talked with ConvergenceRI said that they were puzzled by the lack of market support for Flublok; they wondered out loud if the decision by Sanofi Pasteur to purchase Protein Sciences had been part of a “buy to kill” corporate strategy.

Fluzone, a competing high-dose flu vaccine, is also manufactured by Sanofi Pasteur; there is a much higher volume of doses of Fluzone vaccines available in the marketplace, more than a million doses compared with some 300,000 doses of Flublok.

ConvergenceRI had attempted to reach out to Sanofi Pasteur to inquire if there were a possibility to provide Rhode Island with a quantity of doses of Flublok as a potential public health intervention, given the severity of the flu season, based on conversations with a number of providers who had expressed interest. No response has been received.

Next year in Rhode Island?
In conversations with providers, insurers and practitioners from across the health care landscape, many expressed a lack of knowledge about Flublok.

At a recent check up, ConvergenceRI’s primary care provider, wearing a protective mask, said that she had not heard about Flublok, and quickly looked it up on her computer.

A communications spokeswoman for Blue Cross & Blue Shield of Rhode Island also said she had never heard about Flublok, and promised to check with the chief medical officer.

An emergency room physician working at Rhode Island Hospital and Miriam Hospital said that they had not heard about Flublok; neither had a key member of the R.I. General Assembly.

CVS does not offer Flublok, Tonya Davis told ConvergenceRI, after checking with colleagues. Davis, who is working with the Governor’s Task Force on Overdose Prevention and Intervention, said she had never heard about Flublok.

There is a potential for Flublok to become available in Rhode Island as part of a decision about vaccine purchases made in conjunction with the Vaccine Advisory Committee, according to Joseph Wendelken, communications spokesman with the R.I. Department of Health.

“A cell-based vaccine will be included in our order for the 2018-2019 flu season,” Wendelken told ConvergenceRI.

At the next Vaccine Advisory Committee scheduled for April, members will discuss the potential of purchasing three flu vaccines targeted for older adults: Fluzone High Dose, Flublok and Fluad. The committee will consider adding one or more to the Fluzone High Dose vaccine that is already on the state supplied vaccine list.

The expectation is that the manufacturers will present evidence about the relative efficacy of their flu vaccines, which will potentially create an interesting dynamic: Sanofi Pasteur will be presenting evidence about two of its products, Fluzone High Dose and Flublok.

Gail Skowron, president of ID Management Partners, an infectious disease consulting company, spoke recently with ConvergenceRI about vaccine efficacy, or VE.

“There is more to vaccine efficacy than egg-adapted changes,” she explained. “Vaccine efficacy depends on host immune response [which is often less in the elderly]; the match between the input [of protein in the] vaccine strain and the circulating virus; and egg-adaptive changes [which are not seen with cell-propagated vaccine virus].

In order to maximize the immune response [and vaccine efficacy], Skowron continued, it might require the use of a higher antigen dose, such as Fluzone High Dose, or Flublok, or the use of an adjuvant, such as Fluad.

Without expressing a preference, Skowron said that a cell-propagated vaccine such as Flublok potentially offered a more nimble technological approach.

Take-home message
As an important takeaway, Skowron cited the commentary by Dr. Peter Hotez, dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston, as quoted in an article in MedPage Today, regarding concerns about the lack of vaccine efficacy in the current flu shot.

“These results [reported by the CDC that only 26 percent of pediatric flu deaths occurred in vaccinated children and that the risk of ‘medically attenuated’ influenza illness in children was reduced by 59 percent among vaccinated children] confirm my earlier concerns that public health messaging this year was too focused on the low efficacy of the vaccine in preventing flu infection, rather than preventing flu deaths,” Hotez said, as reported by MedPage Today. “This message was sadly encouraged by the antivaxxer community. The public health community in general [was] not sufficiently visible in the media about the importance of getting vaccinated.”

Editor’s note: ConvergenceRI is not expressing a consumer preference or recommendation for the choice of Flublok as a flu vaccine.


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