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Tuesday, August 2, 2022

Biden Continues to Test Positive for COVID, His Doctor Says

 U.S. President Joe Biden continued to test positive for COVID-19 on Tuesday and will maintain his isolation procedures, but he is feeling well and does not have a fever, his physician said in a memo released by the White House.

"The President continues to feel well, though he is experiencing a bit of a return of a loose cough," his physician Kevin O'Connor said. "He remains fever-free and in good spirits."

Biden, 79, had just emerged from isolation on Wednesday last week after testing positive for COVID for the first time on July 21. He tested positive again on Saturday in what O'Connor described as a "rebound" case seen in a small percentage of patients who take the antiviral drug Paxlovid.

Paxlovid is an antiviral medication from Pfizer Inc that is used to treat high-risk patients, such as older patients.

The White House said on Monday that Biden was feeling fine and looking forward to getting back on the road.

https://www.usnews.com/news/top-news/articles/2022-08-02/biden-continues-to-test-positive-for-covid-his-doctor-says

Paxlovid rebound happens, though why and to whom are still a mystery

 As an emergency department physician in New York, I often field calls about medical issues from family members, friends, and even friends of friends. Since the Covid-19 pandemic began, the number of these calls has dramatically increased.

The latest slew of these, about Paxlovid and rebound Covid-19 — which President Biden now apparently has — has revealed the confusion surrounding this phenomenon for me, my physician colleagues, and at least one Nobel laureate.

I recently got a call from my friend Joachim Frank, who shared the Nobel Prize in Chemistry in 2017, about his rebound Covid after doing what he was supposed to do: taking Paxlovid as his doctor had prescribed.

Then I heard from my brother-in-law, Gary, that he had experienced Paxlovid rebound as well, then my friend Dave, then friends of friends of friends. I began to wonder how rare this really was: At least a subset of my contacts was beginning to wonder if taking the medication had really helped them, or just prolonged their illness and all the logistics that come with a diagnosis of Covid-19.

The Centers for Disease Control and Prevention sounded the alert about rebound Covid in May. It described patients with Covid who, after being treated with the antiviral Paxlovid, initially became symptom-free and in many cases had negative tests for SARS-CoV-2, the virus that causes Covid-19, but then got sick again. The same phenomenon occurs with another antiviral oral medication to treat Covid, Lagevrio (molnupiravir) and at the same rates, but Lagevrio may not be as effective as Paxlovid and therefore has not yet become as much of a household name.

ince the CDC alert, there have been a number of rebound studies, including a recent investigation of 92 million people nationwide showing rebound rates of less than 6% for Covid infection — and less than 1% for hospitalizations after Paxlovid treatment — most occurring in unvaccinated people and in those with underlying medical conditions.

To offer my patients, family members, and friends the best advice possible, I reached out to David Ho, a virologist at Columbia University in New York who first figured out how HIV replicates and the go-to genius on many current virus issues. By chance, he and a family member had recently experienced Covid rebound and, in fact, feature prominently in research findings of his that will soon be published in the New England Journal of Medicine. “I am Patient #2 and my family member is Patient #3,” he told me.

In an email exchange, Ho characterized the frequency of rebound Covid as “common enough,” and that with more and more people taking Paxlovid, the number of rebound Covid cases will likewise increase.

My emergency medicine physician colleagues are seeing tons of it.

Joachim Frank had been in Germany for the 71st Lindau Nobel Laureate Meeting — a gathering of 30 or so Nobel laureates and select young scientists. His days in Lindau were the culmination of five weeks he and his wife, Carol Saginaw, spent in Europe, packed with lectures, dinners, and scientific seminars. On July 3, he told me he felt like a “rush going through my head, comparable to fever fantasies I had when I was a child,” and had developed a cough and highly sensitive skin all over his body — it hurt so much he could barely touch it. After a rapid test was positive for SARS-CoV-2, he began a five-day course of the three-pill Paxlovid regimen: two pink nirmatrelvir tablets and one white ritonavir tablet twice a day.

With full understanding of the research showing Paxlovid helps reduce hospitalization and death in his and other age groups and among people with preexisting conditions, starting Paxlovid was a no-brainer for him. With the exception of the “awful metallic taste” — likened by my brother-in-law to the taste of a can of Coca-Cola that has been sitting open for a month — and some stomach upset, he had no complaints with the Paxlovid. And it worked. After a day and a half, the cough had disappeared and his skin was no longer especially sensitive.

On the fifth day of the Paxlovid regimen, Frank, who was then testing negative, and his wife, who had been testing negative daily since her husband became ill, flew back to New York. The next day, she felt fatigued and had a cough, and then tested positive; she started Paxlovid too. Frank felt fine and went back to work, though fully masked.

But six days after taking his last dose of Paxlovid, Frank was sick again. That’s when he called me. He was queasy and tired, his skin again too painful to touch, and his Covid test turned positive so quickly he was fearful the control line would not have time to appear.

He had lots of questions for me: Is this rebound Covid? If it is, what does it mean for me? If he was positive again and his wife was now negative after her own illness, did he need to mask around her? Does she need to wait two to eight days after finishing her course of Paxlovid before she can go food-shopping? Do they eat in separate rooms? Is Paxlovid rebound as contagious as the first go-around?

There are no clear and easy answers to these questions, just as there is no solid explanation for how or why Paxlovid rebound occurs. One theory is the virus mutates and develops resistance to nirmatrelvir and ritonavir, the two drugs that are combined to produce Paxlovid.

Ho has his own ideas. He doesn’t think drug resistance is at work and, after he and his team had done viral sequencing, found no viral mutation. He theorizes that Paxlovid is successfully blocking viral replication and disease while the drug is in the body. But what Ho calls an “intermediary form of the virus” starts replicating again once the drugs are no longer circulating.

Ho’s team has also conducted viral sequencing among contacts of rebound cases — information the average person does not get with the yes/no red bar on a rapid test. Family members of people with rebound Covid who then get Covid-19 themselves share the same viral subvariant with their familial contact — which suggests that people with rebound Covid are contagious.

Based on Ho’s theory, it’s possible that people may need to take Paxlovid for longer than five days. Ho tells me that some clinicians are already prescribing for longer treatment periods, but there are no official recommendations — yet.

People with rebound Covid do not seem to be getting terribly sick. Frank had additional days of fatigue and painful skin; my brother-in-law lost his taste and couldn’t smell basil; my friend Dave had three days of a cough. But the rebound prolongs the logistical complications of Covid that can wreak havoc on peoples’ lives, including return to work, caring for children or other family members, travel, and participation in social events.

For me, rebound begs the question: Is Paxlovid worth it? The CDC advisory states in black, bold, and no uncertain terms that, despite the risk of rebound Covid, “Paxlovid continues to be recommended for early-stage treatment of mild to moderate Covid-19 among persons at high risk for progression to severe disease.” But the definition of “high risk” in this situation has been a moving target since the first days of Covid-19.

Someone who is 80 years old with multiple risk factors for severe disease, like asthma, cancer, or heart disease, certainly qualifies as high risk. But whether “high risk” applies to someone who is 65 years old, in great shape, and vaccinated is less clear, even though age has been one of the most-used determinants in Covid-19 treatment. And what about the 35-year-old with asthma? Are they, or even those younger with asthma, at high risk?

Many people opt out of taking Paxlovid, or take a wait-and-see approach. Those who consider the risk of rebound Covid one they don’t care to take may, says my colleague Rebecca Press, an outpatient internist with New York Physicians, be eligible for monoclonal antibodies. Formerly a logistical nightmare to obtain, Press says monoclonal antibodies are now easily available and effective and that infusion teams will now bring the intravenous medication to one’s home and administer it.

Does Joachim Frank regret taking Paxlovid, which led to rebound Covid, which prolonged his isolation, which caused him to miss work and kept him from seeing his grandchildren for at least five additional days? He doesn’t.

But the jury is clearly still out. Although people tend to think of medical care as something that is certain, it is actually a real-time experiment. Paxlovid, like a lot of Covid-19 care, is a reminder of this.

Joan Bregstein is an emergency medicine physician in New York City, a professor of pediatrics (in emergency medicine) at the Columbia University Vagelos College of Medicine, and a medical writer.

https://www.statnews.com/2022/08/02/paxlovid-rebound-mystery/

Dem drug-pricing plan warrants disinformation flag for seniors

 Senate Democrats are moving forward with a falsely advertised drug pricing plan. Liberals, and even maverick Sen. Joe Manchin (D-W.Va.), claim their newest plan will help lower drug costs for seniors and even drive down inflation. As always, however, the fine print says something else. In fact, the scheme would be a disaster for the development of life-extending, life-improving medicines and medical devices. 

Start with the money. The details show their proposal is more about raiding Medicare than it is about lowering their prescription drug costs. There is a $300 billion cut to the Medicare program, much of which would be immediately spent to extend expiring COVID-era emergency ObamaCare subsidies that went to higher-income earners.

That might be helpful to insurance companies seeking to sell more ObamaCare policies to a bigger, newly eligible customer base, but it certainly does not help lower seniors’ drug costs. 

As for the supposed lower drug costs they claim seniors will benefit from, most of those would not materialize for at least three to five years — providing no immediate relief — until the drug pricing provisions have time to take effect. Even beyond this irresponsible “spend now, save later” approach, seniors could find themselves subject to new access restrictions to certain medicines. 

And here’s the kicker: According to the Congressional Budget Office (CBO) and studies from the University of Chicago, patients and families will see fewer new cutting-edge treatments come about as private sector research and development investments dry up.

It’s also important to look at how Democrats are attempting to define “savings.” First, they would fully eliminate a significant Medicare reform that was approved by the Trump administration but has been purposely delayed by President Biden. Centered on negotiated rebates secured — and often kept — by pharmacy benefit managers (PBMs), the so-called rebate rule would have required big discounts on drugs to go directly to seniors enrolled in Medicare almost immediately. 

Furthermore, these discounts would have been applied directly at the point of sale (i.e., local pharmacies, etc.) when individual seniors paid for their prescription medications. However, no new government programs or corporate middlemen would have been needed, so liberal Democrats naturally opposed it. Instead, Biden, House Speaker Nancy Pelosi (D-Calif.) and Senate Majority Leader Chuck Schumer (D-N.Y.) want a government-run program that identifies or “negotiates” potential savings so that they, not seniors, can collect the discounts and decide how to spend the money. That should not be a comforting prospect for seniors. 

Next, Democrats have marketed their plan as a simple process by which the federal government will use its power to negotiate lower drug prices for Medicare beneficiaries. In reality, it is a price-control scheme no matter how it is advertised and will have the same devastating impacts price controls always do: diminished supply of the products in question. Worst, the creation of vital new drugs and treatments would whither. It typically costs $3 billion dollars and 15 years or so of development time to bring a drug to market.

In the Democrats’ plan, government bureaucrats would set a price and tell drug developers to take it or leave it. If they don’t accept Medicare’s offer, they could be subject to as much as a 95 percent excise tax on total sales of a particular medication. That is not negotiation. That is not a counter negotiating tactic, as Democrats suggest. That’s basic economics. 

Because of our free market system, the United States is by far the world’s leading developer of new drugs. Pharmaceutical companies have the opportunity to make a return on investments from their discoveries. Without such a system, we would be without a host of the recent breakthrough discoveries for chronic and rare diseases brought forth over the past decade, including our ability to develop vaccines for COVID-19 in record time

American patients have better access to beneficial drug treatments as a result of our pharmaceutical policies, particularly cutting-edge therapies for cancer and other life-threatening diseases. For example, cancer patients in the U.S. are able to access 96 percent of all cancer medications, while Canadian patients have access to less than 60 percent of them. In many European and other developed nations, breakthrough drugs for cystic fibrosis and other debilitating diseases available for U.S. patients are not made available at all because governments refuse to pay for them.

Although new drugs often can be expensive, due to costly and lengthy development processes, competition in the U.S. continues to drive increased availability of generics, which collectively save patients over $330 billion per year. In fact, about 90 percent of all U.S. prescriptions are for generics, more than in other countries, and they are cheaper here than overseas, about 16 percent less on average. And even more savings on generics are coming about due to innovative enterprises such as Mark Cuban’s Cost Plus Drug Company that cut out the corporate middlemen to lower prices for generics well below what insurers charge. 

The Democrats’ price-setting plan is just as bad now as it was when it was part of President Biden’s failed spending plan and Nancy Pelosi’s failed price control plan before that. It is more a means to raise revenue for liberal politicians than it is an effective way to lower drug costs for seniors. It’s both dishonest in how it is being presented and harmful to the long-term health of Medicare. Liberals in Congress are making a risky bet by siphoning off and spending seniors’ Medicare money first in the unrealistic hope of extorting some savings later. A wise move for vulnerable Democrats would be to fold. 

Steve Forbes is chairman and editor -in-chief of Forbes Media. Follow him on Twitter @SteveForbesCEO.

https://thehill.com/opinion/healthcare/3577999-democrats-drug-pricing-plan-warrants-disinformation-flag-for-seniors/

Otonomy Shares Sink After Stopping Mid-Stage Tinnitus Study

 

  • Otonomy Inc (NASDAQ: OTIC) has announced that the OTO-313 Phase 2 trial in tinnitus demonstrated no clinically meaningful benefit versus placebo for primary and secondary endpoints across all time points.

  • The 153-subject study did show a higher response rate than placebo in a prospectively defined patient subgroup with tinnitus duration of fewer than six months (population studied in Phase 1/2 trial).

  • The overall results do not support further development of OTO-313.

  • "These results were unexpected with a much higher placebo response than observed in the prior Phase 1/2 study," said David Weber, president & CEO of Otonomy.

  • In addition to this trial, the company also reviewed preliminary top-line results for the one-month safety evaluation of higher and bilateral dosing of OTO-313. It did not observe a clear treatment benefit in light of the Phase 2 results.

  • Hence, Otonomy will discontinue working on OTIC-313 and shift its focus to OTO-413 for hearing loss.

  • Enrollment is complete for evaluating higher dosing with top-line results expected in Q4 of 2022.

Signify Health Considers Strategic Alternatives, Including a Sale

 Signify Health Inc. SGFY 6.76% is working with bankers to explore strategic alternatives including a sale, according to people familiar with the matter, roughly 18 months after the healthcare-services company’s initial public offering of stock.

Signify Health, which had a market value of more than $4 billion on Tuesday afternoon, supplies technology that helps health plans and providers with in-home care. It could attract interest from private-equity firms as well as managed-care providers, the people said.

https://www.wsj.com/articles/signify-health-considers-strategic-alternatives-including-a-sale-11659471113

Gilead Boosts 2022 Guidance On The Back Of Its Covid Treatment

Gilead Sciences (GILD) beat quarterly expectations Tuesday and raised its guidance almost entirely on the back of its Covid treatment, Veklury. GILD stock edged higher in after-hours trading Tuesday.

Veklury sales tumbled 46% during the June quarter to $445 million. But that beat forecasts. This year, Gilead boosted its full-year outlook by $700 million at the midpoint. The company now expects Veklury to bring in $2.5 billion in sales this year, up from its prior guidance for $2 billion.

The quarter should help Gilead solidify its position as a value name trading at a low multiple, RBC Capital Markets analyst Brian Abrahams said in a report.

"A solid quarter, with seasonally favorable HIV dynamics looking even better than expected, strength in cell therapy which could increase enthusiasm about that market opportunity in earlier lines, good international Veklury update, solid expense control and revenue/EPS guidance raises," he said.

In after-hours trading on today's stock market, GILD stock rose 1% to $60.15.

Overall, second-quarter sales unexpectedly climbed 1% to $6.26 billion. Analysts expected sales to drop to $5.86 billion. Adjusted profit came in at $1.58 per share, 6 cents better than expected. Profit toppled about 13% due to an upfront payment and a royalty expense related to HIV drug Biktarvy.

Excluding Veklury, Gilead's sales rose 7%. Strong performers included Biktarvy, which brought in $2.56 billion in sales, up 28%. Biktarvy topped forecasts for $2.33 billion to $2.35 billion, RBC analyst Abrahams said.

Across the board, sales of HIV treatments increased 7% to $4.22 billion, helping offset declines for the hepatitis C and hepatitis B/D treatments. Revenue from cell therapies for cancer popped 68% to $368 million.

For the year, the biotech company guided to $24.5 billion to $25 billion in product sales, which excludes revenue from collaborations and licensing. That includes about $2.5 billion from Covid treatment Veklury. Gilead also expects to earn $6.35 to $6.75 per share, minus some items.

GILD stock analysts predicted adjusted earnings of $6.56 per share and $24.59 billion in sales.

https://www.investors.com/news/technology/gild-stock-gilead-earnings-q2-2022/

Paul Offit on His Vote Against Bivalent COVID Boosters

 In the first part of this two-part conversation, Jeremy Faust, MD, editor-in-chief of MedPage Today, talks with Paul Offit, MD, about his recent decision to vote against the bivalent COVID-19 booster shot at a recent meeting of FDA's Vaccines and Related Biological Products Advisory Committee (VRBPAC).

Offit is director of the Vaccine Education Center at Children's Hospital of Philadelphia (CHOP), attending physician in the division of infectious diseases at CHOP, and Maurice R. Hilleman Professor of Vaccinology at the Perelman School of Medicine at the University of Pennsylvania.

The following is a transcript of their remarks:

Jeremy Faust, MD: Hello, I'm Jeremy Faust, medical editor-in-chief of MedPage Today. Thanks for joining us.

Today we are joined by Dr. Paul Offit. He is a member of the FDA Vaccines and Related Biological Products Advisory Committee, the VRBPAC, which is the committee that publicly discusses, and debates, and ultimately votes on recommendations related to the COVID-19 vaccines and their authorization for use.

Dr. Paul Offit, thank you so much for joining us.

Paul Offit, MD: My pleasure.

Faust: Let's start by talking about an article you wrote in the New England Journal of Medicine, 'COVID-19 boosters -- where from here?' You argued, essentially, that these mRNA vaccines in particular were designed to do something very specific, which is to prevent severe disease and deaths, and that they happen to temporarily do what everyone else wants them to do, which is to decrease infections.

It seems to me that a lot of people are looking at boosters and they don't realize it, but they're treating them like they're almost prophylaxis, and I think that, in your view, is not a sustainable way to do things. How do you think this is going to play out?

Offit: I think probably you can trace the confusion back to December of 2020.

In December of 2020, the FDA vaccine advisory committee was asked to consider both Pfizer and Moderna vaccines. Those were two-dose vaccines given 3 or 4 weeks apart, and protection against mild, moderate, and severe disease was 95%. Those vaccines were roughly 95% effective at preventing not only severe illness, but also mild illness.

Then what happened was 6 months later, the CDC did studies showing that protection against severe disease holding up, which is good, but the protection against mild disease was fading -- as you would've guessed -- because protection against mild diseases, for the most part, is mediated by neutralizing antibodies present at the time of infection, and those faded.

So why was it 95% protection against mild disease in December of 2020? Those were 3-month studies. Those participants had just gotten their second dose. So therefore, you sort of had this unrealistic sense of what this was all about. That was the way it was handled, not only by the media, but I think in many ways by public health officials; officials who use words like 'fading immunity' or 'breakthrough infections' when you were seeing exactly what you would expect to see.

Even 1 year later, when studies were done by Mark Tenforde out of the CDC, with just two doses you found that protection against severe disease was holding up.

Then Omicron hit, which was an immune-evasive strain, and caused mild illness even in those who were vaccinated. I think this sort of led to a lot of confusion and ultimately led to a third dose and then to a fourth dose. And I think we used terms like 'fully vaccinated' as compared to 'fully vaccinated and up-to-date,' and I think it would be hard to find 10 Americans who would agree on what it means to be protected against this virus.

Faust: I think that's fair. Now, I actually think this next question is sort of out of order, but I think it's important that we do it first. That is that you are, as I mentioned in the introduction, on the committee -- VRBPAC -- that looks at these questions of what we should do next and makes recommendations, and you voted against the bivalent booster. That is, using a booster that's got some of the old strain and some of the Omicron [strain] in it. You voted against that for the fall. I'd like you to talk us through your thought process and why you think that doing it your way would be better.

Offit: The studies that were presented to us on June 28 of this year, 2022, by both Pfizer and Moderna were done the right way, which is to say they gave people three doses of the ancestral strain vaccine and then the fourth dose was either the ancestral strain vaccine or the fourth dose was a bivalent vaccine. The bivalent vaccine in both cases, for Pfizer and Moderna, was the ancestral strain plus BA.1, the original Omicron strain. They then looked at the difference in those neutralizing antibody responses based on whether you got the ancestral boost or whether you got the bivalent boost.

What they found was -- depending on how the study was done because Pfizer did 30 mcg or 60 mcg and Moderna did 25 mcg for the ancestral and then 25 mcg for the Omicron strain -- they found that the difference in neutralizing antibodies was either 1.5-fold greater against neutralizing antibodies for Omicron if you got the bivalent strains compared to if you just got the ancestral strain, or 1.75 greater, or 1.97 greater.

The implication was that that's good enough; that those statistically significant differences were also clinically significant differences, when we knew that back in December of 2020 -- when you looked at the neutralizing antibody differences between Moderna and Pfizer -- there was roughly a twofold greater neutralizing antibody response for Moderna than Pfizer, but that didn't really matter in terms of protection against severe illness.

So why were we making this difference of 1.5-fold or 1.97-fold greater with the Omicron boost than the ancestral boost? Why were we making that seem as if that was going to be the answer to all our problems? Plus, the BA.1 strain is essentially gone. It's been replaced by BA.5/BA.4 and now BA.2.12.1, which are just Omicron subvariants that are somewhat distant from BA.1.

So where this is settled out is that I think the [Biden] administration is interested in having a bivalent vaccine where one of the strains is the ancestral strain and the other strain is BA.5. And we'll see, but I certainly hope that before they launch that kind of program for the American public, they show clear evidence that there is a dramatic increase in neutralizing antibodies with BA.5 associated with that boost. Because remember, even with boosting the ancestral strain, you do get somewhat of a broadening of immune response as Linda Saif and coauthors showed in a New England Journal Medicine paper at the end of June.

So I think that's the burden that it should be held to because otherwise it's just marketing, right? Otherwise it's like, 'I'm going to give you BA.5 because BA.5 is circulating and therefore it's going to be better,' which theoretically makes sense, but you need to have clear evidence, preferably clinical data, but at the very least compelling immunological data.

Faust: Now, would moving to a bivalent booster just in general be progress against this concern about 'imprinting or antigenic sin'? The idea is that whatever your body sees first, it will sort of narrowly respond to that. Therefore in the future, your body doesn't have as good of a response because of what it initially saw. Does giving bivalent anything actually have some benefit just on those grounds?

Offit: Again, it should be proven, but the imprinting thing was originally defined by a researcher named Thomas Francis, who was working with influenza back in the 50s, and he used the term 'original antigenic sin.' The thinking was this, you can tell when children were born based on the way they respond to influenza -- either natural infection or immunization -- because they respond as if they're responding to that original infection. The original infection that they had when they were children, if they then get a vaccine or a secondary infection, they're responding as if they're responding to that first infection and not recognizing the subtle differences with that either vaccine or natural infection.

That's what you worry about here, that you sort of lock people into this response against the ancestral strain and don't have the chance then to have a broader response.

I will say this though, the ancestral strain is the original strain. It's the Wuhan strain. The one that first raised its head in Wuhan in October/November 2019 has served us well. I mean, all the way through, even including Omicron and the Omicron subvariants, it does appear to continue to protect against serious illness, which is the goal of this vaccine. At least it was the stated goal of this vaccine, but I feel like we're drifting a little bit from protection against serious illness to trying to protect against all illness.

And I would argue that there are some people who can't handle a mild illness. They can't handle it because they have severe heart disease or severe lung disease or because they have out of control diabetes or whatever, so when they get a mild or moderate infection they're more likely to develop a severe illness or because they're immune compromised.

So that's different. That's really not fading memory, it's someone who either never had a very good immune response because they're immune compromised or because of their age they don't make very good so-called cytotoxic T-cell responses, so they're not as able to crowd the infection and keep it as a mild or moderate infection. You could argue that that group may benefit from a boost, if you will, to keep neutralizing antibodies high, to the extent they can make neutralizing antibodies for a few months during the times when these viruses are at peak circulation, you could make that argument. But I think we're sort of not making that argument; we're making the argument of boosters for all. And first of all, I think people are a little weary of boosters at this point.

Faust: Yeah. I mean, the way I'm looking at it is that people who, as you mentioned, have another risk factor for hospitalization probably need to stay what we'd call 'up-to-date' on their vaccine so that they don't encounter mild illness because mild illness has implications for them that they don't have for others. It's not that they'll get severe disease; severe COVID, it's that that mild illness will make something else severe. That's what we keep seeing, and the data are bearing this out. So, absolutely, I think saying up-to-date for older populations makes sense.

I don't think the mRNA vaccines are optimized for this, but they're the best we've got, so that's what we're stuck with for now. But I agree with you that we could kind of spend all of our effort on that group and have huge benefits instead of diffusing the efforts, the money, the signal, for very little in return.

As I think about younger people, some younger people obviously really want doses. They've bought into this idea that these vaccines can eliminate infection. I think you and I agree on this, the benefit for boosting for young people is very transient, if any, but over time I think arguments have been made that say, 'OK, look, there's a lot of good reasons to boost younger people.'

Where do you stand right now? Do you still think that two doses of the ancestral vaccine is sufficient for most people, and have you softened on third doses for younger people? I guess the third question of this three-part is: who do you think right now needs more than two doses?

Offit: I still would argue that for a healthy young person, two doses appears to continue to protect against severe illness. What that third dose does do though for Omicron, meaning BA.1 and the Omicron subvariants, is you do get an increased response against those variants and subvariants.

The question is, does it matter? Because still it looks like you're protected against severe illness, so does it really matter to get that third dose? I would argue 'no.' [But] I think that ship has sailed. I think this is now a three-dose vaccine for the most part, because that's the way the press and the public have handled it, it's the way public administrators have handled it.

But I still would argue, if you looked at that Mark Tenforde paper that was published in Infectious Diseases, what he did was he looked at two doses for 1 year, up through December of 2021 so the vaccine had been out for a year -- so you're looking through the D614G variant, the Alpha variant, and the Delta variant -- and what he found was that protection against serious illness was holding up. And this was for...80% of the people in that group had at least one comorbidity and a significant percentage were over [age] 65. So that was holding up pretty well.

But then Omicron hit, and we clearly have shown that three doses is better than two for Omicron in terms of preventing hospitalization. My question is: who are those people? And I think that's not everybody.

I still think it would be helpful for the CDC to sort of sub-stratify that. To some extent they have; they've shown us that at least 75% of those who are getting hospitalized despite having two doses were in these high-risk groups that we just talked about. So focus on them. I think that is what makes the most sense to me.

Faust: Yeah. If you look at the CDC's readouts -- I think we've discussed this before offline, but I'm not sure we've discussed it in public -- it's actually very difficult to tell the difference between a person who got their second dose a year ago and a person who got their third dose a year ago. So the idea of the three-dose vaccine kind of only makes sense in that in the period of time for which a third dose increases those neutralizing antibodies.

So yes, you could tell the difference between someone who just got a third dose, but you also can't tell the difference between someone who just got a third dose and someone who just got their second dose. What really matters is how far are you out from your most recent dose, and I think that the public is basically not going to keep doing this except for high-risk groups. Is that a fair read?

Offit: Very fair. And I think when we compare vaccinated to unvaccinated or got a two-dose versus three-dose you need to also account for who has gotten naturally infected in the meantime, because that does alter things. And it is knowable, I mean, you can know that by looking at say antibodies against, say, the nuclear protein, which is only going to happen if you've been naturally infected. So I think that also is one of the problems -- controlling for natural infection, which now is common.

I remember when a couple months into this pandemic, Jon Yewdell, who was the head of virus research at the National Institutes of Health, said 3 years from now you're going to have two choices: be naturally affected or be vaccinated.

If you look at some of these recent seroprevalence studies, there was one in JAMA recently, showing that as many as 90% of people have either been naturally infected or vaccinated when they look at the thousands and thousands of lots of people who have donated blood. Now, that's limited by who chooses to donate blood, but I still think it is striking.

Faust: Right. And I think maybe a cognitive shift that I made at some point was that you might not necessarily choose between infection or vaccination, but you have to choose infection with protection or infection without protection. In other words, you walk into that infection or that exposure with a vaccine on board or not, and you want to do that, obviously.

I want to make sure that we don't make incorrect news here. You said that you think it's a three-dose vaccine, but you said that because you think that basically the scientific debate is over because no one is having it. Not because of science support stuff but basically due to marketing, is that correct?

Offit: Yeah. I just got an email today from a mother of a college student who was upset that her child can't go to a certain East Coast school because he hasn't had his third dose. She argues reasonably -- he's a healthy young person, he's gotten two doses, he's a boy who is in an age range where he is at some risk for myocarditis, and I don't think the benefits outweigh the risks here. A perfectly reasonable argument. I agree. I agree with her.

Faust: But I also think that, as my friend Carter Mecher pointed out to me when we discussed this like a year ago, that most people who get a third dose, even in that group of a young, healthy male, most people will be happy with their decision to get a third dose because for 99% it makes no difference. For a small, tiny group it would help; for a small, tiny group it would hurt.

So most people would just be happy with their decision because whatever they did, they think, 'Well, I got a third dose. I did my best.' Therefore the administration is saying, 'Well, look, if it breaks even we might as well just make everybody happy.'

Offit: Yeah. There was an old study that was done at a Canadian racetrack where they asked people to rate their horse while they were on the way up to making the bet, then they asked a different group of people to rate their horse after they'd already made the bet. Obviously, after you already made the bet, you rated it much higher.

But what I loved about that article was the title, which was "Post-decision dissonance at post time."

Faust: Right. Post-vax something or other -- we could do it with that.

The mix and match, the idea of starting with one formulation of Pfizer and then boosting with Moderna, do you think it matters? Certainly, it has a little bit more of an antibody response and more side effects, but on a population level do you think it matters? If someone asks you, 'What should I do?,' what do you tell them?

Offit: Wait for data. I mean, it is interesting to see some of these early reports now of boosting with Novavax, which is a purified protein vaccine that's adjuvanted with the same adjuvant that's used in Shingrix, which is an exceptional vaccine.

If you've already gotten, say, two doses or three doses of an mRNA vaccine and then you get this dose of Nova, the antibody studies, at least the small ones that have been reported so far, look promising.

But again, you ultimately need clinical data, and hopefully the CDC can help generate those data.

https://www.medpagetoday.com/opinion/faustfiles/100026