Pfizer in Practice

This week brought a medical article worth discussing: the New England Journal of Medicine published the results of a study of the efficacy of the Pfizer SARS-CoV-2 vaccine in the real world. The article provides compelling evidence that the vaccine works extremely well.

The data come from Israel, which has been doing a superior job of vaccinating its citizens. As of a week ago, two-thirds of the currently eligible population in Israel had gotten both of the recommended doses (individuals under age 16 and those who have had Covid-19 are not eligible). In Israel, health insurance is mandatory for all permanent residents; they must join one of four healthcare organizations called “funds.” The new study reports data from Israel’s largest health organization (Clalit Health Services) and includes information on a stunning 1.2 million people.

The study’s authors, led by Dr. Noa Dagan, used Clalit's integrated electronic medical record to capture health data for 596,618 people who received both doses of the Pfizer vaccine between December 20, 2020 and February 1, 2021. They then matched them, based on demographic and clinical characteristics, with another group of identical size who had not received any vaccine. Next, they looked at five different outcomes: documented Covid-19 infection; symptomatic Covid-19 infection, Covid-related hospitalization, Covid-related severe illness, and Covid-related deaths. Because the sample was so large, they were also able to collect extensive information about a number of interesting subgroups defined by age or specific co-existing health conditions such as cancer or diabetes.

The article includes an enormous amount of intriguing data. The most exciting results, from my perspective, address outcomes a week or more after receiving the second dose of the vaccine. At that point, the vaccine conferred 94% protection against symptomatic Covid-19 (95 percent confidence interval 87-98), 87 percent protection against Covid-related hospitalization (CI 55-100), and 92 percent protection against severe Covid (CI 70-100).  The efficacy in people over 70 was identical to those in younger individuals, and the rate in people with one chronic health condition such as diabetes was only slightly lower than in people without the condition. 

These numbers strongly resemble the results that Pfizer and BioNTech reported to the FDA in their application for emergency approval.  But, as the study authors point out, Pfizer drew its conclusions based on 44,000 people; the Israeli study is based on 1.2 million people. As a result, when Pfizer calculated the efficacy against severe Covid-19, they drew on a total of 10 cases (one of whom had been vaccinated and 9 of whom had not been); when the Israelis calculated the risk of severe Covid, their estimate was based on 229 cases, vastly increasing the credibility and certainty of the calculation. Moreover, Pfizer’s data was based on the somewhat artificial conditions of a clinical trial: for example, the subjects were all highly motivated to optimize their health and may have regularly worn masks and practiced social distancing; the Israeli study drew on real life experience, in which participants’ behavior reflected community norms.

The new study, like all studies, has its limitations. It excluded people living in nursing homes and medical personnel working on Covid units in the country’s hospitals, arguing that the rate of the disease in their particular communities, i.e. the nursing home or the Covid ward, was highly atypical. The study was performed during a period when the South African variant was very rare in Israel so we cannot draw conclusions about the efficacy of the vaccine against this strain. The information on the ability of the vaccine to prevent Covid-related deaths is limited because of the short follow-up period: there were nine Covid deaths in the fully vaccinated and 32 deaths in the unvaccinated group, but these numbers might change when more time elapses. The data on deaths may also be difficult to generalize as Israel has an unusually low case fatality ratio: in Israel, according to Johns Hopkins' "Our World in Data," is currently 0.7 percent whereas in the U.S. it is 1.8 percent.

Some of the study’s greatest strengths are also potential weaknesses: the “real world” nature of the investigation means it is an observational study rather than a randomized controlled trial, raising the possibility that the differences in outcomes between the vaccinated and the unvaccinated were related to some factor other than their vaccination status. Despite these limitations, the study provides very encouraging information.

The fact that the Israelis could carry out their study sends another message over and beyond the efficacy of the Pfizer BioNTech vaccine. The study could only be conducted because Israel did a good job acquiring and distributing vaccine. Early on, the country developed mass vaccination sites. Since everyone is enrolled in a health plan and the plans all have electronic records, there was no need to waste as much time on bureaucracy as we do in the U.S, where more time is spent filling out forms than on administering the shot. The study could only be conducted because of Israel’s electronic health records, which assured that information about who got what dose when, and the age, sex, and chronic medical conditions of each individual was digitally recorded. Finally, the entire rollout was centrally coordinated, assuring efficiency and consistency: from the outset of the pandemic, the Israeli Ministry of Health collected Covid-related data from all four health plans, negotiated to purchase vaccine from Pfizer, and organized distribution. The good news reported in the NEJM article is a result both of the biological properties of an mRNA vaccine that was designed in record time to deal with an international health crisis of enormous proportions, and of the characteristics of a health care delivery system that can actually deliver.

Vaccine Mania

Last Monday, the public woke to the news that the COVID-19 vaccine developed by Pfizer and BioNTech, which has been undergoing testing since the end of July, appears to be working. That is very good news for older people, who have been hardest hit by the coronavirus epidemic, as well as for the younger population, which is bearing the brunt of the current surge in cases. And the news is very timely, as the cumulative number of cases in the U.S. is now over 11 million, with the number of new cases every day higher than ever before. But what, exactly, do we know about how effective this vaccine is likely to be?

The statistic that is cited in the news reports is that to date, the vaccine is 90 percent effective. What that means is that among the 94 people enrolled in the Pfizer/BioNTech study who were diagnosed with symptomatic infection, only 10 percent or about 9 people had received the vaccine; the other 90 percent or about 85 people had been given placebo. This is very encouraging, since the clinical trial enrolled 44,000 volunteers, half of whom received active vaccine and half of whom received placebo: it is very unlikely that such a large differential could have happened by chance. On the other hand, there’s much we don’t know.

We don’t know, for instance, whether the 90 percent effectiveness rate will hold up in all age groups. The study population does include older individuals—the plan was to try to ensure that 40 percent of those enrolled would be over age 55, though it’s unclear what percent would be in the highest risk group, those in their 80s and older. But we don’t know anything about the age or other risk factors of the 94 people who were diagnosed with coronavirus. Since older people todare being far more risk averse on average than their younger counterparts, it’s possible that none of the 94 people with infection identified so far are older adults.

We also don’t know whether the vaccine protects people against developing asymptomatic infection. From a clinical perspective, it’s more important to know whether the vaccine prevents people from developing symptoms, but from a public health perspective, we would like to know whether the vaccine keeps the virus at bay just enough so they remain asymptomatic but not enough to prevent them from transmitting the disease to others. Since asymptomatic transmission accounts for many cases today, it would be desirable to know whether the vaccine allows people to become asymptomatic carriers. We are not going to know the answer to that question as the study protocol does not call for enrollees to be tested for COVID-19 unless they develop symptoms.

Finally, we don’t know how long immunity will last, assuming the promising early results are maintained when the study is completed, which will happen once 164 subjects have been diagnosed with COVID-19 (the pre-specified endpoint of the study). 

What does all this mean for everyone who is eagerly awaiting a vaccine to end this long period of isolation, anxiety, and loss? If the final data, when evaluated by the FDA, possibly by early December, do lead to approval and licensing of the vaccine, older people should be vaccinated as soon as possible—assuming the age-specific effectiveness holds up. 

How will life change after you have been vaccinated? First, it should be stressed that “being vaccinated” means receiving 2 injections, 3 weeks apart. The vaccine effectiveness is being measured starting one week after receipt of the second dose, so you cannot expect protection until one month after your first shot—and you should be sure to get both shots. Second, while 90 percent effectiveness is pretty good, it’s not perfect. No vaccine is perfect, so don’t wait around for a better one. While you will face a much smaller risk of becoming sick with Covid-19 if you have been vaccinated than if you have not been, how likely you are to encounter the virus will depend on how widespread it is in the surrounding community. If, to take the extreme but unfortunately not entirely improbable case in which the rate of infection in the community goes up ten-fold, then if your risk by virtue of vaccination goes down ten-fold, the net improvement is zero. Of course, if the rate in the community goes up by a factor of ten and you haven’t been vaccinated, your risk also goes up by a factor of ten. In short, you are much better off with the vaccine than without it, but how much better off you will be will be determined by what is going on around you.

So, yes, there is good news about vaccines and yes, you should get the shots as soon as they are available, assuming the early results are confirmed and apply to older people. But don’t throw out your masks and don’t expect to go to movies and concerts or other large indoor gatherings just yet.

As I prepare to publish this blog post, news is breaking about a second vaccine made by the pharmaceutical company Moderna in partnership with NIH. More to come about these results in my next post….

Have We Been Barking Up the Wrong Tree?

More of my blog posts deal with dementia than with any other subject and the news about Alzheimer’s disease over the years has been largely dispiriting, so who would have thought that I would leap at the opportunity to write about a new diagnostic test. But with so much of the medical literature relentlessly focused on COVID-19, it’s reassuring to realize that research on other subjects is continuing. The new study does not report a treatment, let alone a cure for Alzheimer’s disease. Furthermore, the prospect of screening healthy individuals to determine their future risk of developing progressive cognitive impairment is ethically fraught. Nonetheless, in the current climate, this report is good news.

It’s good news, and not just because it indicates that not all medical scientists have retooled as corona virus researchers, though it does that. It’s good news, and not just because it means it will be possible to target intervention studies to high risk individuals will permit studies to be carried out on smaller numbers of people and over a shorter period of time, though it means that. It’s good news because it shines a bright light on a long-neglected character in the Alzheimer’s story, the tau protein. 

Back in 1906, when Alois Alzheimer peered into his microscope at tissue from the brain of a patient who had died of the disorder of cognition that would one day bear his name, he identified two unusual substances that he described as plaques and tangles. The plaques, which were located between neurons, would ultimately be found to be composed of a protein known as amyloid. The neurofibrillary tangles, which were located inside the nerve cell bodies, would eventually be identified as a protein called tau. These two substances have been recognized as the hallmarks of Alzheimer’s disease for over a century.

For years, the roles of amyloid and tau were hotly debated. Some researchers felt that amyloid was the result of Alzheimer’s; others were confident it was the cause. Some scientists were more interested in studying amyloid; others directed their efforts towards tau. But over the course of the last 25 years, amyloid has gained the upper hand. Study after study has sought to improve cognition in Alzheimer’s disease by ridding the brain of amyloid-laden plaques—and each time, the approach failed. 

A great deal of excitement was engendered by immunotherapy back in 2001: the idea was to stimulate the body to create antibodies against amyloid with what was essentially a vaccine—but the study had to be stopped because a subset of patients developed meningitis. Then there was enthusiasm about the use of monoclonal antibodies. Several such antibodies have made it to phase 3 trials in which their efficacy was compared to placebo. In 2014, two studies of Bapineuzumab showed no benefit. In 2018, Solznezumab was tried for individuals with mild Alzheimer’s and it was unsuccessful. In the same year, additional negative results were reported for Verubecestat in people with mild to moderate Alzheimer’s. 

All these negative studies don’t exonerate amyloid. Maybe the trials are initiated too late in the course of these disease’s development. Maybe the dose is too low. But with anti-amyloid strategies repeatedly striking out, I can’t help but wonder, as have others who know much more about the science than I do, that we’re looking at the wrong target.

Which is why the new study that focuses on tau is exciting. The authors found that their tau antibody test was able to diagnose Alzheimer’s disease as well as or better than more invasive existing tests—when they used the test in patients all of whom had some kind of neurodegenerative disease. That is, the test did well in answering the question: is this person being tested more likely to have Alzheimer’s or, say, Parkinson’s? That’s a very different question from: is this person normal or does he have Alzheimer’s? Not only was the population in which the test was studied composed exclusively of patients with some neurologic condition, not only did the population include a much larger proportion of people with Alzheimer’s than would be found in the general population, but the subjects were far from ethnically or racially diverse. So, it’s a long way from the article in JAMA to a widely useful diagnostic test.

Despite the test’s preliminary nature, it is a compelling piece of evidence that tau should get more attention. Two weeks before the on-line publication of the JAMA study, a small Swiss pharmaceutical company, AC Immune, announced that together with Johnson & Johnson, it was launching a trial of a vaccine designed to stimulate the body to produce antibodies against tau—leading its stock price to soar by 18.9 percent. Just a few weeks earlier, the giant Swiss pharmaceutical company, Roche, announced it, too, was investing in the development of an anti-tau vaccine. 

It’s too early to say whether the attack on tau will fizzle, much like the previous attacks on amyloid. But maybe, just maybe, it will be a rousing success.