Now Hear This

On November 9, we learned that the preliminary data from the Pfizer/BioNTech COVID-19 vaccine trial are very promising; exactly one week later, we got similarly good news from the ModernaTX/NIH study.  What do the Moderna data show and how do they compare with the Pfizer data?

Moderna began enrolling patients last summer and has recruited 30,000 volunteers, half of whom received two doses of vaccine and half of whom got placebo, in both cases at 30-day intervals.  

The subjects, adults over the age of 18, were divided into 3 groups: people age 65 or older; people under 65 with known risk factors for coronavirus; and people under age 65 with no known risk factors. The principal outcomes that the researchers are tracking are the ability of the vaccine to safely prevent symptomatic COVID-19 infection and the capacity of the vaccine to stimulate antibody production in recipients. In addition, the researchers are looking at whether the vaccine can prevent severe COVID-19 infections and whether it can prevent asymptomatic infection (as measured by markers for COVID indicating current or previous infection despite the absence of symptoms).

The newly reported results are based on the 95 enrolled subjects who have thus far been diagnosed with COVID-19. Being diagnosed with COVID-19, according to the definition in the study, means having a positive PCR (polymerase chain reaction) nasal swab after developing symptoms consistent with the disease. What we know is that of these 95 individuals, 5 had received active vaccine and 90 had received placebo. We also know that 20 of the 95 people with the illness were over age 65 and that 11 people developed severe disease, none of whom had been vaccinated. While the specific numbers have not been reported, Moderna has asserted that the efficacy was the same among the different age groups as well as among various ethnic groups (or, more accurately, given the very small numbers of sick people, they were unable to detect any differences).

What we don’t know is the duration of the protective effect. We don’t yet know whether the vaccine prevented asymptomatic infection, although we should know something about its capacity to do so when the endpoint of the study is reached, namely when 151 enrolled individuals have been diagnosed with symptomatic disease. And we don’t know whether the vaccine is effective in children.So, how does the Moderna vaccine compare to the Pfizer vaccine?  

They are both mRNA vaccines, a type of vaccine that has never been approved for human use. The efficacy rates reported thus far are extremely similar: from a statistical standpoint, the 95 percent efficacy quoted by Moderna is not any different from the 90 percent efficacy quoted by Pfizer, given the small number of sick patients.  

Both vaccines have to be kept cold to remain viable, but shipment and long-term storage of the Pfizer vaccine has to be at 70 degrees below zero Centigrade while long-term storage of the Moderna vaccine can be at 20 degrees below zero Centigrade; on arrival at your local drug store or physician’s office the Pfizer vaccine can be refrigerated at normal temperatures for up to 5 days while the Moderna vaccine can be refrigerated at normal temperatures for up to 30 days without losing potency. 

The Pfizer vaccine has been tested in children; the Moderna vaccine has not so we just don’t know whether it will work in this age group. Finally, the Pfizer vaccine is to be given as two doses separated by 3 weeks while the Moderna vaccine is given as two doses separated by 4 weeks; efficacy was tested by Pfizer beginning 1 week after the second dose and by Moderna beginning 2 weeks after the second dose. These differences may not reflect actual differences in the two vaccines, simply different protocols instituted for studying them. In sum, it looks as though the two agents are very similar except for differing refrigeration requirements. 

Quite apart from the biochemistry of these vaccine candidates and the data on their efficacy, what do we know about Pfizer and Moderna? 

Pfizer is the Goliath of pharmaceutical companies. As of March, 2020, it was the largest drug company in the world, as measured by revenue, with annual revenues of $51.75 billion. It has experience in producing vaccines and in recent times was responsible for the development of one of the major pneumonia vaccines. But Pfizer is also a leading offender among the major drug companies in unethical and illegal behavior. In 2009, it achieved notoriety for the largest settlement ever made by a drug company with the Department of Justice: It agreed to pay $2.3 billion for fraud involving the atypical antipsychotic drug Geodon and the painkillers Bextra and Lyrica. It would lose the distinction in 2012, when GlaxoSmithKline settled with the DOJ for $3 billion. 

Despite signing a “Corporate Integrity Agreement” in 2009, a quick internet search reveals that Pfizer continued to engage in bad behavior: in 2011, it paid $14.5 million for the illegal marketing of Detrol; in 2016, it paid $784.6 million to resolve a lawsuit involving Medicaid fraud; in 2018, Pfizer paid $23.85 million to resolve a suit over Medicare kickbacks. It’s worth noting that most of the big pharmaceutical companies have engaged in fraud, including such names as Johnson & Johnson, Eli Lilly, Abbott, Novartis, and Merck. They seem to regard playing fast and loose with the rules as part of doing business.

If Pfizer is the Goliath of the industry, Moderna is the David of the industry—or was until it went public in 2018, raising $604 million through the sale of its shares and gaining a valuation of $7.5 billion despite never having brought a product to market.

Moderna began as a small biotech startup in 2010 and has focused on mRNA vaccines since its inception. Questions have been raised about the integrity of the company in light of its culture of secrecy and the high-stress environment created by its CEO. 

Some have even wondered whether Moderna would be the next Theranos, the unicorn ultimately exposed as a fraud, a story detailed in the chilling account by WSJ investigative journalist John Carreyrou in “Bad Blood: Secrets and Lies in a Silicon Valley Startup.”

Moderna has partnered with NIH (specifically the National Institute of Allergy and Infectious Diseases) in its COVID-19 vaccine project. Hopefully, the involvement of a highly reputable, not-for-profit, academically oriented organization has provided a layer of oversight to the drug company.

So far, the data from both the Moderna/NIH trial and the Pfizer/BioNTech trial look very auspicious (BioNTech, by the way, is a German company devoted to developing immunotherapies, principally as treatment for cancer; it has partnered with Pfizer for years in a thus far unsuccessful effort to produce an mRNA vaccine against influenza). Let’s hope that the record of American Pharma in general, and the questionable past behavior of both principal companies in particular, prove irrelevant to our health.

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….

The Corona Century: Looking Backward, Looking Forward

For over, 50 years, epidemiologists had been expecting “the big one.” Like earthquakes in California, influenza epidemics have become an inevitable part of the landscape. From year to year, influenza mutates; every so often the strain is particularly virulent and it produces a world-wide pandemic, as happened in 1918 and, on a smaller scale, in 1957, 1968, and 2009. Every year, scientists scrutinize the prevailing type of influenza, anticipating that one day we will see the resurgence of a virus as virulent as the one that killed upwards of 50 million people in 1918-1919. Granted, we have vaccines today that prevent or attenuate many cases of the flu, we have antiviral medications with modest degree of efficacy against influenza, and we have sophisticated supportive respiratory treatments such as ventilators, none of which were available in 1918. As a result, any new influenza pandemic is unlikely to be as devastating as its counterpart 100 years ago—but nonetheless, could wreak havoc in our globalized world. So, it was very surprising when, in March, 2003, scientists in search of the causative agent of the newly described respiratory illness known as SARS (Severe Acute Respiratory Syndrome) peered through their electron microscope and discovered, not influenza, but corona virus.

Coronaviruses had first been identified in the 1960s; they were known to infect cattle, pigs, rodents and chickens; in humans, they were associated with about fifteen percent of colds, but not with any more illnesses. But there it was, with its characteristic crown-like ring of proteins—the agent responsible for the mysterious disease that had killed clusters of health care workers, families, and residents of an apartment complex, principally in China and Hong Kong.

Once the genetic identity of the virus had been established, the race was on to figure out where it came from. It was pretty clear that the virus had jumped species, making SARS a “zoonosis.” What species it came from was never definitively established, though palm civets and raccoon dogs sold in the wild meat markets of Guangdong province, China, to consumers eager for an “exotic” meal are the leading candidates. Growing evidence suggests that the true animal reservoir of the SARS virus (SARS-CoV-1) is the bat, with animals such as civets serving as an intermediary.

Due to good epidemiologic practice, the biology of SARS-CoV-1, and luck, SARS disappeared. The World Health Organization (WHO) announced the containment of the epidemic in early July, 2003, less than four months after it first issued an international alert about the dangers of the disease, and less than a year after it first appeared in China in November, 2002. A total of 8098 people developed the illness, of whom 774 died, or just under 10 percent.  All told, the virus appeared in 39 countries. Only China, Hong Kong, Singapore, and Canada had 50 or more cases each. The world breathed a sigh of relief; epidemic prevention programs were developed on paper—and shelved.

And then, in 2012, coronaviruses were back. Or rather, a new coronavirus made its debut: MERS-CoV (for Middle East Respiratory Syndrome). Originally found in Saudi Arabia, it soon travelled to the rest of the Middle East. And stayed there, with the only significant outbreak anywhere else in the world found in Korea in 2015 after the index case had travelled to the Middle East. Unlike SARS, MERS has never disappeared. It remains endemic in the Middle East, where it kills 35 percent of those it infects. Its animal reservoir is probably also a bat, but from bats it infects is camels, and from camels it reaches people. By limiting contact with camels and using case isolation and contact tracing, the total number of confirmed cases in the last eight years is only 2500. More lethal than its SARS-CoV-1 cousin, but less easily transmitted, MERS put coronavirus firmly on the map as a pathogen to be reckoned with, but a relatively minor one, compared to, say, the viruses causing Ebola or AIDS.

Until November, 2019, when yet another atypical pneumonia appeared in China, an illness that would prove to be caused by another coronavirus, this one dubbed SARS-CoV-2. The rest is history, although history that is still unfolding. As of October 30, 2020, according to WHO-COVID Dashboard, there have been a total of 44.59 million cases worldwide, with 1.18 million deaths.  In the US alone, there have been 8.83 million cases and 227,045 deaths. The pandemic is far from over, with the US reporting 81,599 new cases per day. This latest variant of the coronavirus has proved far more successful than its relatives: it seems to have found the ideal balance of transmissibility and lethality, which has enabled it to achieve far more extensive community spread than any previous coronavirus. COVID-19 (the name given to the disease caused by SARS-CoV-2) kills roughly 2.5 percent of those who are diagnosed with the condition, less than SARS (10 percent) and much less than MERS (35 percent), though in all three cases, the mortality is far higher in individuals over age 65. In addition, it ingeniously developed the ability to spread from asymptomatic hosts, allowing it to escape prompt detection and thus limiting the effectiveness of isolation to contain its spread.

Supported by governments and the WHO, several pharmaceutical companies along with university research labs are scrambling to produce a safe and effective vaccine. But with cases of COVID-19 continuing to rise in many parts of the world including the US and Europe, the prospects for an end to the pandemic any time soon are not good.  Several nations have reintroduced lockdowns: France just announced it would shut down from October 30 until December 1 and Germany declared a partial shutdown for roughly the same period. With the whole world suffering from pandemic fatigue—except, perhaps, Taiwan, which just celebrated its 200^th day in a row without a single locally transmitted COVID case—it’s hard to even think about life-after-COVID except in terms of “going back to normal.” Odds are that when the disease finally goes into retreat, we will breathe a collective sigh of relief and not want to think about viruses. But that would be a grave mistake.

The current century has already seen three coronavirus epidemics, each with a different variant of this wily microorganism. Most likely, all three normally live in bats and jumped from bats to non-flying mammals and from those mammals to humans. Coronaviruses are RNA viruses, known for their extraordinarily high mutation rates—as much as a million times higher than human mutation rates, which means they will continue to develop new variants. And these new variants will now and then develop the capacity to infect people, both because humans have encroached on the territory of animals with whom we previously had little contact and because global warming drives animals out of their traditional habitats and into new arenas that are occupied by humans. The really successful ones, like COVID-19, will be transmissible from asymptomatic individuals. They will have the ability to spread to other humans quickly, without or before killing their new human host. And then they will be spread by humans from person to person, from household to household, from country to country, from continent to continent.

In short, there is no reason to believe that even if we manage to kill or contain SARS-CoV-2, we will have seen the last of the coronaviruses. However appealing it will be to resume normal life, we must not let down our guard. We have to begin now to plan for the next outbreak. We must be sure to learn from our experiences. That means, first and foremost, taking basic preparedness measures such as stocking up on personal protective equipment. It means replenishing the supply of masks and gowns, even if we go for ten years without an epidemic, just in case. 

Planning for the future, as explained by public health lawyer Lawrence Gostin, entails investing in a robust public health system. Such a system must be able to institute traditional measures such as quarantine of those exposed to disease, isolation of cases, social distancing, and mask-wearing. We have to support scientific research so that new pathogens can be identified, tests developed, and treatments tested in a timely fashion. We must restore the FDA and the CDC to their former grandeur, two organizations that, until the current pandemic, were the envy of the world because of their sophistication, wisdom, and integrity. We have to engage in surveillance, constantly monitoring bats and other species for new diseases. 

We must recognize that we live in an interconnected world, which means collaborating with other researchers and laboratories across the globe, including those of China and of the World Health Organization. And when a new, disease-causing virus appears, we need to demand transparency from our leaders and our scientists: an informed public, armed with the tools of public health and the fruits of medical science, is crucial to combatting the threats that will inevitably appear.