We’ll start out talking about COVID-19 just to get it over with. The way it looks now, we’ll be needing to stay on top of that tiresome subject for a good long time, even after all of us are fed up with hearing about it. As you know, that particular snake keeps changing its spots, and all the evidence we have is that it will continue to do so. A hopeful but reasonable expectation is that as it goes on mutating, the new variants will become less threatening, until (as someone or other said) it’s no worse than a bad cold.

The most recent variants of concern, as they are officially termed, are the BA.4 and BA.5 Omicron subvariants, which are on the rise at this time.

What do we know about Omicron BA.4 and BA.5?

Variants and subvariants tend to emerge where infection and transmission rates are highest, which unsurprisingly coincide with those parts of the world where vaccination rates are lowest. BA.4 and BA.5 emerged in South Africa early in 2022, and the first cases were detected in the US on March 30 and March 29 of this year.

Those two variants are on the uptick at present. According to CDC estimates, in early June BA.4 accounted for just 5.4% of cases, and BA.5 for 7.6%. The previous Omicron subvariants, BA.2 and BA.2.12, are currently the dominant strains, accounting for around 83% of new cases nationally. However, according to Dr Jacob Lemieux of Massachusetts General Hospital, we’re probably past the peak of the BA.2/BA.12.2 waves, but the BA.4 and BA.5 waves are still ahead of us.

The new case rate in the United States has more than tripled in the past ten weeks, from just under 30,000 new cases per day at the end of March to about 100,000 new cases per day currently. The number of deaths per day has not changed much, fluctuating between 250 and 400 per day, which is much lower than during the winter surge when Omicron first appeared.

As with the earlier Omicron subvariants, BA.4 and BA.5 are highly transmissible. However, they appear to bring about mild disease. Unlike Delta and other previous variants, they appear to attach to tissue in the upper respiratory system, particularly the nasal passages. These variants can cause fever and general malaise (French for “feeling lousy”), but seldom result in serious illness, hospitalization, or need for respiratory assistance. Temporary loss of the sense of taste or smell has been observed. The relation between these subvariants and long COVID has not yet emerged.

BA.4 and BA.5, like the previous Omicron variants, appear to get around the immunity offered by previous COVID infections. Vaccination works somewhat better (in particular in that it protects vaccinated people from serious illness even if they become infected), and persons who have been vaccinated and boosted have a good deal of protection. A second booster improves that protection by a considerable margin.

As we have discussed in these postings several times, for the virus, being highly transmissible while causing mild disease is a survival characteristic, and therefore we should expect to see the coronavirus evolving in that general direction. For a virus to spread maximally, it should be highly transmissible and result in the host (i.e., the patient) being capable of transmitting the virus for a long period before developing symptoms. From the perspective of the virus, making the host seriously ill is emphatically not a survival characteristic, since it will result in the host being isolated and not transmitting the virus to other potential hosts.

What do we have to look forward to? Almost certainly, more subvariants, perhaps increasingly transmissible but causing less severe illness. Another possibility is that further boosters will become available, perhaps adapted to the changing structures of the coronavirus variants. Will we be getting annual COVID shots, the way we (or some of us) get annual flu shots? That remains to be seen.

Vaccines for kiddies under 5

In the past few days both the Moderna and Pfizer/BioNTech vaccines for the youngest of us have been judged by FDA advisory committees to be safe and effective. Currently in the US, the 18 million children under 5 years of age are the largest unvaccinated group.

The importance of getting young children vaccinated has as much to do with the health of the rest of us as it does with their own health. Since serious illness with COVID-19 is very rare in children under 5, one might ask, why is it worth the bother – and the risk – of getting them vaccinated? One answer is that if a young child gets infected, he/she can very effectively pass on the infection to a susceptible adult. We see this all the time. Little Myrtle brings home a strep infection from school and passes it along to grandma, who is taken to the hospital and may or may not recover. The same transmission links can take place with COVID, and with the same results.

The FDA has said that the Pfizer/BioNTech data suggest that three doses of their vaccine are more effective than two, but it was hard to draw definitive conclusions, because in the 1,415 children who received three doses in the clinical trial, very few developed COVID – 8 in the placebo group and 2 in the treated group. According to their statistical requirements, a total of 21 cases needed to emerge to evaluate the efficacy of three doses of vaccine versus two doses.

Despite these statistical uncertainties, on Wednesday, June 15, the FDA’s Vaccines and Related Biological Products Advisory Committee voted unanimously (21 – 0) to grant EUA for use of both the Pfizer/BioNTech and Moderna vaccines for children – Pfizer’s three-dose vaccine for children 6 months through 4 years old and Moderna’s two-dose vaccine for children ages 6 months through 5 years. Previously, FDA advisory committees have voted unanimously to grant EUA to both the Moderna vaccine, for children up to age 5, and the Pfizer vaccine for children ages up to age 6.

Which is better? The Pfizer vaccine perhaps has an advantage regarding the efficacy of the vaccine, although as you read above, the data fails to reach statistical significance. However, on another front, there may be an advantage to the Moderna vaccine in terms of timing. The Moderna vaccine consists of two shots given 28 days apart, and maximum protection sets in about two weeks after the second shot, so kids are well protected six weeks after the first shot. The Pfizer vaccine requires three doses. The second dose is given 21 days later, and then the third dose is 60 days after that. All told, the Moderna vaccine provides maximum protection about six weeks sooner than the Pfizer vaccine.

Paxlovid uncertainties

Paxlovid (nirmatrelvir/ritonavir, from Pfizer) has been demonstrated to reduce the risk of progression to severe COVID-19, including hospitalization and death, by 89%; however, this degree of risk reduction pertains only to high-risk unvaccinated patients. For vaccinated patients and those not at risk of severe outcomes, Paxlovid’s benefits are not so clear.

In standard-risk patients, the risk reduction of hospitalization or death was 51%, but that endpoint did not attain statistical significance. Of 1,153 patients enrolled through December 2021, there were five incidents of hospitalization or death with the drug versus 10 with placebo (0 vs 1 death, respectively). An analysis of 721 vaccinated adults — all of whom had at least one risk factor for progression to severe disease — showed a non-significant 57% reduction in hospitalization or death with the drug versus placebo (3 vs 7).

Another uncertainty is “Paxlovid rebound” – a condition where a person’s COVID-19 symptoms recede and the person tests negative for the virus, but then after a period of perhaps a couple of weeks, the symptoms return and the person tests positive once again. In the clinical trials conducted by Pfizer that initially led to Paxlovid’s FDA approval, the proportion of subjects that experienced return of symptoms or reinfection was quite low, around 2%. Information about Paxlovid rebound at this point is entirely anecdotal, but some observers suggest that the frequency of that occurrence is higher than 2%. Whether the rebound is in some way related to the action of Paxlovid or to a characteristic of the coronavirus is not known.

A recent study in nearly 500 high-risk patients, 93% of whom were fully vaccinated, found that only four patients experienced rebound symptoms. All the rebound symptoms were resolved by means of treatment that directly addressed the symptoms. The risk factors that affected those four patients included coronary artery disease, chronic obstructive pulmonary disease, diabetes, obesity, chronic kidney disease, hypertension, and a history of prostate cancer.

One possibility being investigated is that while Paxlovid effectively deals with the patient’s symptoms, it does not entirely clear the virus from the patient’s body. Remaining virus particles can then reproduce and cause the symptoms to resume. A longer course of treatment may be needed.

We may be sure that the attention of the medical community is on this. We’ll hear more.

Is monkeypox a threat of the same magnitude as the coronavirus?

Doc Gumshoe’s answer is a reasonably confident “no.” That does not mean that there’s nothing more to say about this disease, which, by the way, the “authorities” are planning to rename, because the word “monkeypox” and the origins of the disease in Africa are thought by some to be racially disparaging. (Do we have to add “monkey” to the list of words that we must not must not say? That list is growing.)

The CDC reported a couple of days ago that there is no evidence that transmission of monkeypox is airborne. All the cases they have seen so far come from direct physical contact, and most of the first 45 cases detected so far in the US are in men who have had sex with men. You won’t contract monkeypox from being in a crowded setting without a mask.

As of June 22, a total of 156 cases of monkeypox infection had been identified in the US. The global total is about 3,400 cases, with 3,500 more being evaluated. The highest case loads are in the Democratic Republic of the Congo, where the totals are about 1,500 cases and 72 deaths.

Rachel Walensky, the CDC’s director, said “All of the cases we’ve seen to date in this outbreak are related to direct contact, either through skin-to-skin contact or through bed sheets.” She acknowledged the possibility of droplet transmission, where the virus is transmitted by means of large respiratory droplets, such as coughing or sneezing, but not by means of aerosols. Airborne transmission is usually defined as small viral particles that become suspended in the air and can stay there a long time. This is not a threat with monkeypox.

Cases of monkeypox in the US have been reported in patients who do not develop the flu-like symptoms that have been typical in monkeypox cases in Africa. Some US cases present with a rash around their genitals or anus. Walensky urged clinicians to be suspicious of any “blister-like” rash, and cautioned not to rule out those with sexually transmitted infections, as there have been reports of monkeypox co-infections with syphilis, gonorrhea, chlamydia, and herpes. The CDC is working to expand upon the clinical symptoms of monkeypox to include some more unusual ones, such as proctitis (inflammation of the rectum) which can cause pain during defecation.

Monkeypox was discovered in Africa in 1958 by scientists doing research on monkeys. The virus is similar to the virus causing smallpox, although it causes much less severe disease. Other animals in Africa such as squirrels and bats can also harbor this virus.

The usual early symptoms of monkeypox may include fever, fatigue, headache, and enlarged lymph nodes, although as we said, many of the US cases move on to the characteristic monkeypox rash that usually emerges a few days later. This rash often starts on the face and then appears on the palms, arms, legs, and other parts of the body. Some recent cases began with a rash on the genitals. Over a week or two, the rash changes from small, flat spots to tiny blisters similar to chicken pox, and then to larger, pus-filled blisters. These can take several weeks to scab over. Once that happens, the person is no longer contagious, since it is mostly through contact with the blisters that the monkeypox virus is transmitted.

Although the disease is usually mild, complications can include pneumonia, vision loss due to eye infection, and sepsis, which sometimes is a life-threatening infection.

Vaccination against smallpox, which was nearly universal up until the 1970s, provides approximately 85% protection against monkeypox. In the US, 95% of the population had been vaccinated against smallpox, but in 1972 the disease was declared eradicated in the US, and vaccination ceased. At this time in all probability, only persons about 60 years of age or older are vaccinated against smallpox – about 20% of the US population.

Even though WHO has declared that smallpox has been eradicated, the US government has stockpiled doses of the smallpox vaccine in the event of an emergency, such as the escape of the smallpox virus from a laboratory where it has been preserved for possible research purposes. Also, in 2019 the FDA approved a vaccine for people at high risk for smallpox or monkeypox. The vaccine is called Imvamune, Imvanex, or JYNNEOS, from Bavarian Nordic, a company specializing in vaccines. The latest news is that Bavarian Nordic is ramping up production of their vaccine.

There are no specific treatments for monkeypox, but several agents may be effective.

• Tecovirimat (TPOXX, from Siga Technologies) is an antiviral drug approved by the FDA for the treatment of smallpox in adults and children. The CDC has an expanded access protocol, sometimes known as “compassionate use,” that permits the use of stockpiled tecovirimat during a monkeypox outbreak.
• Cidofovir (Vistide, from Gilead) is approved by the FDA for treatment of cytomegalovirus retinitis in patients with AIDS. Stockpiled cidofovir can also be used in case of a monkeypox outbreak under the compassionate use protocol.
• Vaccinia globulin intravenous (VIGIV, from Camgene Corp) is licensed by the FDA for treatment of complications following smallpox vaccination. An expanded access protocol from the CDC allows for the use of stockpiled VIGIV for the treatment of viruses including monkeypox.
• Brincidofovir (Tembexa, from Chimerix) is an antiviral medication that was approved on June 4, 2021 for the treatment of human smallpox disease in adult and pediatric patients, including newborns. CDC is currently developing an emergency use authorization to help facilitate use of brincidofovir as a treatment for monkeypox.

In my personal opinion, the reason we have been hearing so much about monkeypox is that we – along with the rest of the world – are more than a bit spooked about COVID-19. When the news about monkeypox first surfaced, a common reaction was, “We’re in for another deadly pandemic!” But the evidence so far says, “Not so fast!”

There are several reasons why monkeypox is not likely to be a threat at all similar to COVID-19. As we said above, the monkeypox virus does not spread nearly as easily as the coronavirus. Close contact is required – skin to skin, or skin to a surface, such as clothing or bed linens, that have been in contact with the pustules of an infected person. A person is not capable transmitting the infection until symptoms appear. And since the chief symptoms are skin lesions, it is not hard to tell whether a person is infected. Transmission is not apt to take place in cases of brief and casual contact.

The most recent outbreak of monkeypox in the US took place in 2003. According to the CDC, almost 50 people in the Midwest caught the disease. The source was contact with pet prairie dogs that had been boarded in a facility that also kept animals imported from Ghana.

One additional bit of good news about this outbreak is that this specific strain of monkeypox is from West Africa, which is associated with a death rate that is much lower than the Congo Basin strain. The West African strain’s death rate in Africa is between 1% and 3%, whereas the Congo Basin’s death rate is about 10%. That’s in Africa. The comparable death rates in other regions are not known.

News from the cancer front

Cancer research continues at an ever-increasing pace. PubMed lists more than four and a half million papers on the subject, and more than 90,000 clinical trials are currently on-going. A good deal of the new research is one of three broad areas:

• Modifying the patient’s own immune system to attack cancer cells. This approach uses CRISPR CAR-T methods to edit the patient’s own T-cells in such a way that these cells seek out and destroy the specific cancer cells attacking the patient.
• Targeting radiation therapy by attaching particular molecules to receptors that are expressed by certain cancers. These molecules carry radioisotope atoms that can damage and destroy cancer cells, but without damaging neighboring cells that do not have those receptors. This form of therapy is termed “radioligand therapy.”
• Locating and targeting molecules called transcription factors that turn healthy cells into cancerous cells. These dangerous proteins can be tagged in such a way that the healthy cell’s own mechanism for disposing of harmful materials can be turned against those harmful proteins.

We have discussed gene editing several times in past posts. The first of these news items concerns a case where this strategy has proved successful in pancreatic cancer, a notoriously hard-to-treat cancer.

That case was the subject of a paper in The New England Journal of Medicine. (“Neoantigen T-Cell Receptor Gene Therapy in Pancreatic Cancer,” Leidner R et al. N Engl J Med. 2022 Jun 2;386(22):2112-2119). The patient was a 71-year-old woman living in Florida whose pancreatic cancer was first detected in 2018, three years after her symptoms first appeared. She was fatigued, lethargic, and had periods of intense pain, but no specific tumors showed up on any scans.

When the tumor – a 3.5 centimeter mass in the head of her pancreas – first appeared, she initially underwent chemotherapy and then a surgical procedure called “the full Whipple,” in which the head of the pancreas, the first part of the small intestine, the gall-bladder, and the bile duct are removed. Following the Whipple procedure, she had chemotherapy, radiation, and more chemotherapy.

The cancer was no longer present in what remained of her pancreas, but cancerous nodules had metastasized to her lungs. That required more chemotherapy and more radiation therapy. In 2020 she entered a clinical trial in Pittsburgh that employed immunotherapy as a means of attacking cancer tumors.

The cancer tumors shrank to some degree, but only temporarily. They grew back. During this trial, she learned that her specific cancer was caused by a mutated protein labeled KRAS, which is implicated in as much as one quarter of all cancers.

KRAS (kirsten rat sarcoma viral oncogene homologue) is a gene that forms a protein that is involved in a number of cell signaling pathways controlling growth, maturation, and death. Mutated KRAS genes have been found in non-small cell lung cancers, colorectal cancers, and – as in this case – pancreatic cancers. As many as 95% of all pancreatic cancers have been found to be associated with mutated KRAS genes. These have been considered especially challenging targets, since cancer drugs have repeatedly failed to have any effect on these genes or the cancers that they cause. They have sometimes been labeled as “undruggable.”

When she got the information about the role of the KRAS gene in her metastatic cancer, she found out about a clinical trial that was taking place in Oregon. The trial was a “proof of concept” trial, to test whether genetically programming the patient’s own T cells in such a way that they could recognize and kill the specific cancer cells that were present in the patient’s system. That involved harvesting her T cells and editing the T cells’ genetic material using those gene editing techniques that have been recently developed. (We have discussed gene editing via CRISPR-Car T in previous posts and will certainly return to that subject.) These modified T cells are then grown in the laboratory and reintroduced to the patient, where they will hopefully target and eliminate the cancer cells.

The patient travelled to Oregon, and on June 14, 2021, her treatment began. Within a month, the cancer tumors in her lungs had shrunk by about two-thirds and were too small to biopsy. They have continued to shrink, and on May 25, 2022 she had another scan. The oncologists now believe that the spots on her lungs consist of dead cancer cells.

The patient now has none of her previous symptoms. She says she feels great.

At this point, the investigators are not claiming complete victory. The treatment of this specific patient can be considered “proof of concept” – treating a metastatic cancer that had reached a stage previously thought to be beyond treatment, and achieving clear remission is a demonstration of the effectiveness of using edited T cells to treat cancers of that type. The procedure does not guarantee success – a man with pancreatic cancer has undergone similar treatment which did not work for him. It clearly depends on the specifics of editing the genetic material of the T cells and tailoring that editing to the specific cancer cells. There is obviously much more to be learned about this pathway to treating cancers that have been, up to now, about as deadly as they come.

A new frontier in cancer screening?

The cancer screening tests now in common use look for cancer cells in the breast, cervix, colon, and prostate. When clusters of cancer cells are found using the existing tools, the cancers are treated surgically and also with chemotherapy. However, about 73% of persons who die of cancers have cancers that were not able to be detected by standard tests.

The new tests employ a different approach. Instead of looking for cancer tumors, they look for bits of cancer DNA or proteins associated with cancers, and in that way these tests may be able to predict cancers at a much earlier stage, when the likelihood of eliminating the cancer is much higher. Being able to spot and attack cancers earlier should, in theory at least, greatly reduce the number of cancer deaths.

One company, GRAIL, has developed a test which they call Galleri. Their claim is that the test will be able to identify about 50 different cancers in the earliest stages. They are marketing the test directly to the public based on a provision allowing marketing based on laboratory (in vitro) approval rather than on clinical trials. It has been noted that a clinical trial to determine whether testing the public at large would result in a reduction in the number of cancer deaths would require enrolling more than a million healthy adults and would take ten years or longer to report results. The costs of such a trial would be colossal.

GRAIL and another outfit, Exact Sciences, are proposing that every Medicare patient should have a cancer screening test annually. GRAIL’s price for their test is $949, which would just about bankrupt Medicare.

On an individual basis, the new cancer test was effective in detecting pancreatic cancer in a 77-year-old patient early enough so that it could be treated by surgery, chemotherapy, and radiation. At this time the patient has no detectable signs of cancer. Pancreatic cancer is seldom detected at a stage where treatment has a good chance of being successful. The woman described above had the good fortune of finding a successful innovative treatment even though her cancer was not detected until three years after symptoms had first appeared.

In addition to the enormous potential costs to Medicare and the healthcare system as a whole, there are other warning signs relating to the prospect of society-wide cancer screening using these tests. One is that it is by no means clear that all the early-stage cancers detected would be susceptible to treatment. Another is that a certain proportion of those early-stage cancers would never progress to the stage of being life-threatening. However, once a potentially deadly cancer is detected, arriving at a decision not to treat the cancer is difficult. For example, some patients whose prostate cancer is thought not to be life-threatening are sometimes followed on a “watchful waiting” basis, where the progression of the cancer is carefully monitored and treatment is initiated only when the cancer is judged to be life-threatening.

Screening for prostate cancer by means of tests for a prostate-specific antigen (PSA) has been criticized for much the same reasons. A positive PSA leads to a biopsy of the prostate, which is invasive, and can also lead to potentially unnecessary treatment. Prostate cancer progresses slowly and many men die of other causes before the cancer progresses enough to be genuinely threatening. The recommendations of the USPSTF (US Preventive Services Task Force) have led to a great reduction in the numbers of men receiving the PSA test. But this reduction has led to a substantial increase in the numbers of men whose prostate cancer has metastasized and is no longer treatable by the most effective current methods. Therefore many men continue to opt for the PSA test.

It is certainly likely that the GRAIL and Exact Sciences will detect some cancers that will respond to treatment and that would not have been detected early enough by other methods. These new tests could certainly save some lives. The decision whether to employ these tests on a society-wide basis will be very difficult. However, there is no good reason that individuals should not decide whether to have these tests on their own.

A new breast cancer treatment greatly increases survival rate in a group of patients

In the past few years, we have heard a great deal about the success of drugs that target women with a form of breast cancer triggered by a mutant protein known as HER2. Women with this form of breast cancer now do very well with treatment with a drug called Herceptin (trastuzumab, from Genentech). However, only about 15% to 20% of breast cancers are HER2 positive. The rest – the large majority of breast cancers – have very low levels of the HER2 mutant protein and do not respond to treatment with Herceptin.

A new drug, combining trastuzumab with another agent, deruxtecan, was developed by AstraZeneca and Daiichi Sankyo. Trastuzumab deruxtecan is now tradenamed Enhertu.

In a clinical trial conducted at Memorial Sloan Kettering Cancer Center in New York and the Cleveland Clinic, involving 557 patients with low HER2 metastatic breast cancer, the patients who were given Enhertu survived more than six months longer than those who received standard chemotherapy. Dr Halle Moore of the Cleveland Clinic said, “It is unheard of for chemotherapy trials in metastatic breast cancer to improve survival in patients by six months.”

While an additional six months of survival is by no means equivalent to a cure, in the context of a form of metastatic breast cancer where no previous treatment had shown any efficacy, it is a very positive sign. The results in women who are diagnosed with low HER2 breast cancer at earlier stages of the disease, before metastasis, are likely to have much better outcomes, including the possibility of recurrence-free remission, which is the term for the best possible cancer treatment outcome.

What we can take from this is that cancer treatment has evolved enormously since the days when the options were “cut, burn, or poison.” That was short for surgery, untargeted radiation, and chemotherapy using drugs that were toxic not only to cancer cells, but to normal cells. Surgery has been enormously refined by improved scanning methods that permit the surgeon to localize the cancer with great accuracy. Radiation can be precisely targeted to avoid damage to healthy tissue Chemotherapy now addresses very specific types and subtypes of cancer. And our own immune defenses can be modified to attack cancers. We can look forward to further progress along these lines.

Optimism in women is linked to a longer life span

This optimistic morsel is based on a study in 159,255 participants enrolled in the Women’s Health Initiative. The women in this study enrolled at ages 50 to 79 between 1993 and 1998. The study followed them for up to 26 years.

The 25% of these participants who were judged to be the most optimistic were likely to have a lifespan that was 5.4% higher than the 25% who were the least optimistic. The optimistic quartile also had 10% greater likelihood of surviving past 90 years. These trends held true after taking into account demographics, chronic conditions, and depression. Lifestyle factors, such as regular exercise and healthy eating, accounted for less than a quarter of the optimism-lifespan association.

A previous study had also found that optimism was linked to longevity, but because that study had examined a predominantly white population, researchers at the Harvard T. H.
Chan School of Public Health included participants from diverse populations whose mortality rates are higher than white populations. Including a non-white demographic did not alter the results: optimistic individuals tend to live longer.

Being an inveterate optimist myself, I welcome the news.

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I left a lot of questions unanswered in the most recent Doc Gumshoe on Alzheimer’s disease, mostly about specific drugs that might be beneficial in treating AD. In some cases I had the distinct sense that the questioner was more interested in how the stock of the pharmaceutical company would fare than how the actual drug would perform. I will try to venture my opinion on whether the drug itself has promise, but my opinion on the prospects for the stock are worthless. My experience tells me that one bad result can torpedo the prospects for a drug.

A little story: in bygone days I was working on physician education material on juvenile idiopathic arthritis involving what everyone thought was a highly promising drug. Then along came a report that in one clinical trial there had been evidence that the drug was associated with “suicidal ideation.” Mind you, no suicides occurred. But the suicidal ideation report was enough to tank the drug and cancel my assignment. If we had bought the company’s stock based on my guess that the drug was going to be a hit, it’s my wife and I that would have taken the hit. So no guesses on my part.

But keep those questions coming anyway! Best to all, Michael Jorrin (aka Doc Gumshoe)

Disclosure: Of the companies mentioned above, Stock Gumshoe publisher Travis Johnson owns shares of Grail parent Illumina. He will not trade in any covered stock for at least three days after publication, per Stock Gumshoe’s trading rules.