Thoughts About Immunity and Booster COVID-19 Vaccine Doses

The recent announcement by the Biden Administration that fully COVID-19 vaccinated adults would be offered booster vaccine doses 8 months after their 2nd dose prompted a lot of thinking and my doing a lot of explaining about immunity and vaccines. 

I wanted to think a little on paper to try to explain what immunity means, what to expect from a vaccine, and draw some conclusions regarding the impending booster program.

So, what is important about COVID-19 vaccines? Their most important aspect is their ability to prevent severe disease, hospitalization, and death. That is what they were designed to do, and they are doing it brilliantly with a combination of antibodies and T-cells. Indeed, the FDA authorization was based on the ability of the vaccines to stop disease (i.e. symptoms) not clinically silent infections. Hospitalized COVID patients are, for the most part, not vaccinated. There has not been waning of the ability of vaccines to prevent these outcomes (though the White House said it “could”) despite crude Israeli data that cannot be taken as evidence given the statistical paradox present. 

The human system is very complex and hard to simply describe. We have innate (or ready-to-go non-specific immunity) and a more targeted specific type of immunity that takes time to develop called adaptive immunity. Adaptive immunity “adapts” or is directed towards specific pathogens. In broad strokes, there are two aspects to adaptive immunity: humoral (or antibody) mediated immunity and cell-mediated immunity. Both are very critical and work in concert. A major component of cell-mediated immunity are T-cells. There are various types of T-cells including T-cells that can kill infected cells, T-cells that orchestrate the operation of the immune system, and T-cells that dampen inflammation. 

 The most common evidence cited for the need for boosters is waning antibody levels. However, this is not – in and of itself – enough. First, we do not know what level of antibody (and the rarely accounted for T-cell immunity) is needed for immunity. We also do not have clinical evidence of true vaccine failure against important outcomes like hospitalization. There is non-peer reviewed data from Moderna showing higher efficacy with higher antibody titers but importantly, as the paper states, it is limited by the fact that efficacy against severe COVID was not assessed.

 It is well known that antibody levels fall and then spring back up post-exposure (to the virus or the vaccine). That is how the immune system works – it is anamnestic. It “remembers” after the primary response and mounts a heightened response that staves off severe illness using both T-cells and antibodies in the secondary response. We fully expect antibodies to fall as time from exposure to vaccine or infection increases and we fully expect them to rise upon re-exposure. This isn’t vaccine failure; it’s just how the immune system works. That, infections in the vaccinated are generally mild is evidence of this process working.

When the CDC recommended a modification of the primary immunization series for the immunocompromised – which is distinct from a booster – it did so based on clinical evidence that amongst the relatively rare COVID hospitalizations of vaccinated individuals, the immunocompromised were overrepresented (~45% in a non-peer reviewed paper). Additionally, a study in solid organ transplant patientsrevealed not only did they, as expected based on experience with other vaccines, fail to mount a robust (or sometimes any) antibody response but had a 485X increased chance of COVID hospitalization versus someone without a transplant. That type of clinical evidence was then integrated with data on 3rd doses of mRNA vaccines increasing antibody levels in these populations. 

With this booster recommendation to the public, none of that type of clinical data appears to be available for analysis. It is even unclear 

Vaccines are not bug zappers; they are not forcefields. That breakthrough – the term itself falsely connotes vaccine failure – infections are mild is a vaccine success (even as they may increase in frequency). We must remember it is disease not clinically irrelevant infections we are targeting and that is done with 1st and 2nddoses, not 3rd’s. COVID is an endemic respiratory virus, it cannot be eliminated or eradicated. There is marginal utility in the general healthy population getting booster vaccinations at an 8-month interval. It is currently unclear that a 3rd dose will diminish the rare transmission risk posed by the fully vaccinated which prompted CDC guidance on masks to be modified. Granted, there is little harm but is chasing mild infections in the fully vaccinated an important task when a substantial proportion of the eligible population of this country does not even have one dose. Will this change the trajectory of the pandemic in the US or the world? Does putting 3rd doses in the arms of the heavily vaccinated change the situation in Mississippi? 

There may come a time when boosters are needed and it’s important to be proactive and have streamlined approval and distribution pathways, but I don’t think that time is 8 months.

Superman, Where Are You Now?

Each year, to mark the anniversary of DA Henderson's death, I write a blog post posing infectious disease and epidemiology questions that I wish he were around to answer. There usually are myriad public health threats that we have to face each year, but this year is a little different. The COVID-19 pandemic is the insoluble problem I wish he were here to fix. There are so many aspects of this response that have gone wrong and I have to think that part of it is because his voice is no longer part of the dialogue. I could never imagine DA deferring or subordinating his judgment in a situation like this. If DA were around, I believe his booming voice — infused with the confidence, moral authority and scientific certitude from being the man who rid this planet of smallpox — would have been sounding the alarm in January. DA’s would be an eminent voice that could not be ignored, could not be spun, and could not be misunderstood. He — as I witnessed countless times — had no problem or reservation about upsetting political leaders, describing them with choice (and accurate) adjectives, and would never be one who would express fealty. Just imagine what the world would be like if we acted in January instead of pursuing the non-strategy of evasion.

There are so many questions I would want to ask him about this pandemic. Here’s just a sampling.

1. What would have been the optimal strategy for the US in January, February, and March? Would it have been, as I have advocated, aggressive testing of all compatible syndromes, hospital preparedness, and targeted public health interventions? Would that have prevented the events in NYC from spiraling out of control and the cascading chaos?

2. What is the way forward now with an uncontrolled pandemic and a vaccine months away (in the best case scenario)? What is the most important thing we must do now? Is it a harm reduction approach that recognizes we will never go the way of Taiwan?

3. What is the best way to counteract the attacks on expertise? How does the CDC get restored to its prior position ?

4. What does this mismanagement portend for a more severe pandemic caused by an avian influenza virus? Which, of the myriad missteps, is the one most critical to fix?

5. Are paper-based cheap quick “contagiousness” tests a pathbreaking solution?

6. How should the vaccine be ultimately allocated? How should priority groups be decided?

7. What happens to polio eradication, guinea worm eradication, and measles control?

I suspect all of of us who were fortunate enough to be mentored by DA like to imagine he would agree with our own positions on the pandemic. While that is obviously impossible to know, I do think what is more likely (and more valuable) is that his mentees are likely thinking about the pandemic using a method he bequeathed us with. That method, as I practice it, involves thinking long-range, looking for historical clues, integrating every piece of new knowledge, keeping the full context, providing actionable guidance, and prioritizing the most important tasks in multifaceted complex problems.

Many of us who knew DA always ask ourselves and each other “What Would DA Do?” I think we ask this because we know if we could do just that, it would make all the difference.

COVID19: A Path Forward

COVID-19 presents the most pressing infectious disease challenge we have faced in over a century. If predictions are correct, this virus will exact an enormous toll in terms of death, hospitalization, and disruption. It will stress hospitals, panic populations, and alter life. Healthcare providers will not only be infected but be faced with unfathomable decisions in a setting in which standards of care may be altered.

It did not have to be this way.

In about 1997, DA Henderson — the man who eradicated smallpox– warned of the looming threat of pandemics and infectious disease emergencies as he founded a think tank dedicated to preparing the country. In the years since, the anthrax attacks, SARS, avian influenza, the 2009 H1N1 influenza pandemic, Ebola, and Zika confirmed this threat, and gave us the opportunity to learn more about it. Pandemic preparedness professionals, like myself, constantly wrote, spoke, and conducted exercises to help prepare the country, identify shortcomings, and advise policymakers. In 2018, I specifically, wrote about the pandemic potential of respiratory viruses and the need for diagnostic testing. Indeed, when the story of this pandemic is written, the handicapping of our response by inadequate diagnostic capacity will be a major theme.

Such advice, delivered over the span of decades, was not properly heeded and today, we live in the world created by inaction, short-range thinking, and a continual cycle of panic and neglect, while our reports gather dust in desk drawers.

The unprecedented challenge we face with COVID-19 is the predictable result of years of neglect when the biosecurity budget was less than that for military marching bands.

The results of that neglect are manifest today.

If we were to design a scenario in which a disease is allowed to spread rampantly throughout the country what better way would there be than to first deny its significance, create restrictive testing criteria that cements the disease as exclusively travel-related, ignores the need to test and isolate those with mild (yet communicable) cases, and delimits the ability of laboratories to develop their own testing. It is almost as if we extended hospitality to COVID-19. The events of this pandemic have played out like a train heading to imminent disaster.

Now, because of perennial inaction, we face the specter of hospitals in crisis, rationing of care, deficiencies of personal protective equipment, and possibly hundreds of thousands of death.

Driven by panic at a crisis they ignored for too long, policy makers are considering imposing mandatory prolonged social distancing measures, the cascading effects of which may be worse than those of the virus itself. Economic shutdowns, travel bans, border closures, rising unemployment, shortages of vital goods — all predicted in numerous tabletop exercises — are what we now face.

Plans of prolonged, enforced confinement aimed at preserving life at any cost are premised on a misunderstanding of human life and what makes it worth living. When discussing treatment options with a patient, I often invoke the concept of “quality of life”. Patients regularly choose to take on some risk to their longevity in order to preserve or enhance their quality of life. Individual preferences and shared decision-making with physicians guide medical decision making and also should apply to each individual’s decision regarding the degree of social distancing that is appropriate for them.

A degraded quality of life, particularly over time, itself generates its own risks of death. If the lockdown is prolonged, we can expect increases in deaths from cancer, cardiovascular disease, stroke, mental illness, and substance abuse. How many cancers will metastasize while colonoscopies or biopsies deemed “elective” will be postponed?

Quality of life consists largely in the ability to engage in the activities that make up our lives, and central to these activities is work. Most of us need to work to support ourselves, and many people, including myself, derive meaning from their work. Moreover, humans, as a species, survive by productive work. Jobs cannot be easily parsed into “life-sustaining” and “non-life-sustaining” enterprises. All work consists in the creating of something we need to sustain human life physically and psychologically. Some of these needs are more acute than others, but all contribute to our ability and will to live. Stopping people from working is like depriving a limb of blood flow. Though action is sometimes necessary in an emergency, irreparable and irreversible harm will occur if it is prolonged. A prolonged freeze of the economy — even in the face of a deadly pandemic — will cause a long-term damage far greater than any purported benefit.

If a prolonged, enforced retreat from life is not the right way to fight this disease, what is? Until a vaccine is developed, I recommend the following five measures.

1. Voluntary social distancing with cocooning: It is necessary — and critical for high risk groups — to be vigilant about minimizing the risk of viral spread. Each individual and institution should take specific actions, consistent with their own hierarchy of values, to not be an unwitting host to a virus that may damage themselves or others. Specific clusters of vulnerable populations such as nursing homes should be cocooned from everyday life to greatly minimize their chances of exposure. When social distancing is mandated by law it should exist for as short as possible of a time frame and to allow as much flexibility to individuals as possible.

2. Hospital preparedness: To meet the demand of the expected surge of patients, resources should be directed to expand hospital capacity. While many of these activities will take months to scale-up, the pandemic will likely continue for a year or more. Some activities that can be started now can be expected to have an impact in the days or weeks, others will benefit us months from now. Among the measures the federal government with state, local, and private partners should begin immediately are constructing new hospitals, reopening recently closed hospitals, and using alternative care sites. The federal government, again in collaboration with private partners, must also quickly scale up the production of mechanical ventilators and personal protective equipment (PPE) for healthcare workers.

3. Diagnostics: To allocate scarce medical resources and to make informed decisions about social distancing in different communities, we need to do dramatically more diagnostic testing across the country. Towards this end, we should stop requiring all tests to go through comprehensive testing to be considered ‘CLIA-waived’ and suitable for use at the point-of-care. If a test can be reasonably performed at the point-of-care, it should be granted that status. There also exists, at this time, home diagnostic testing technology for influenza that can provide results for patients at the point-of-care in their own home. Though not yet approved, it can be adapted to test for the novel coronavirus and quickly made available. Such testing will help individuals infected with the virus to know their status and self-isolate. Such home diagnostic technology can also provide knowledge of community disease prevalence. Performance of serological testing to determine extent of infection and the level of immunity in a community is also a priority activity.

4. Healthcare worker augmentation: The potential shortage of healthcare workers can be partially alleviated by immediately expanding the scope of practice of nurse practitioners, nurse anesthetists, physician assistants, paramedics, pharmacists, psychologists, and emergency medical technicians. Currently, a patchwork of disparate regulations occurs in states and it is long since past due that these medical professionals be able to practice to the full extent of their training and ability. It is also important for states to extend healthcare worker license reciprocity across all 50 state lines.

5. Right to Try: As new medical countermeasures are developed for COVID19, it is crucial that they be studied in rigorous randomized control trials to determine their efficacy and safety. However, individuals’ right to try such drugs or vaccines and physicians’ right to prescribe them prior to full approval should not be abridged. “Right to try” should immediately be expanded to COVID19-related products.

The days ahead will be difficult for every American and especially so for healthcare workers. However, the answer to this challenge is not to shrink back in panic but to take decisive action to fight the pandemic, while continuing to lead our lives. In the past infectious diseases claimed more lives per capita than are projected to be at risk from this pandemic, but humans rarely responded by retreating from activity. In the years when smallpox ravaged the planet and rubella crippled babies, humans went to the moon.

Community Spread of nCoV2019: Is Endemicity Possible?

Lately, one of the questions I’ve been asked is how I see the novel coronavirus outbreak ending. It is a complicated question that is hard to answer. One outcome that I think is worth exploring, as a thought experiment, is that the novel coronavirus outbreak ends with the virus become one of the coronaviruses we deal with perennially (i.e. it becomes endemic as a human viral respiratory virus). The trajectory of the virus has demonstrated its capacity for sustained human-to-human spread at a rate higher than SARS. As such, I believe this virus is spreading akin to a community-acquired coronavirus such as OC43, 229E, HKU1, or NL63. With those coronaviruses, a winter/spring seasonality is present. Thus, I wonder if this virus — absent control efforts currently underway that may dampen the seasonality or smooth it— would exhibit this type of seasonality. It has clearly no need, currently, for whatever animal reservoir(s) it jumped to humans from.

It is hard to completely understand severity yet as very limited data is available but it is evident from observing case counts and death counts that this virus has at maximum an intermediate coronavirus fatality rate. That is, it lies between the community acquired coronaviruses and below SARS. I have seen some estimate it’s fatality rate to be 1/50th of that of MERS. It does appear, from early case studies, that deaths cluster in older adults with comorbidities.

The WHO today stated that they believe control measures are still thought capable of halting transmission and perhaps these efforts will be aided by the natural coronavirus seasonality. However, if transmission isn’t entirely stamped out and low-level transmission continues it could be the case that next winter the novel coronavirus appears again as part of the viral respiratory virus cast. If that happens could it be we will just have another sometimes severe respiratory virus to contend with (of course containment should be the goal so long as it is possible). We have examples of these potentially perilous infections in adenovirus 14, adenovirus 7, the AFM-induced EV-D68, and several others. These viruses are hazards to be dealt with seasonally and are challenging with high burdens of illness in some individuals. Another important example is that of the 2009 H1N1 influenza A strain that emerged in the spring of 2009 and displaced the prior H1N1 strain to transition from a novel pandemic strain to an endemic seasonal strain.

I don’t know how the emergency phase of this outbreak will end or how quickly events will either support or reject this idea I proposed but I think there is more than a zero probability that a 5th community-acquired coronavirus has appeared.

A Hypothesis about nCoV2019: Thinking about Patient 1 and Patient 0

As the novel coronavirus outbreak evolves, I have been contemplating and developing various hypotheses. One I think I want to explore in a little more depth involves the timestamp of this outbreak: When did first cases occur? When did this virus end up in humans?

I am asking this because as I look at the trajectory of this outbreak I am beginning to think that maybe this case count reflects large community-based transmission that has been ongoing for some time. I have thought that maybe the cluster at the seafood market was a “red herring” (pun intended) and came to light because of the epidemiologic linkage of patients and I am beginning to increasingly think that it may be the case. The Lancet paper on the 41 seafood market cluster tellingly reveals that patient number 1 had no contact with the market and became ill December 1 — weeks before this outbreak came to light. This suggests that this outbreak had been ongoing since at least November unbeknownst to clinicians. Remember, viral upper respiratory infections and even pneumonias largely go undiagnosed to a specific microbiologic level (to wit, I rounded this weekend and had multiple such cases that defied microbiologic diagnosis even in a nationally renowned quaternary care medical center).

In light of the above, the logical question is: if Patient 1 wasn’t linked to the market, where was the virus acquired? Who is Patient 0? We need serological anitbody-based surveys to see how prevalent exposure to this virus was pre-outbreak detection.

Phylogenetic analysis of the virus suggests a single introduction to humans but little variation in the limited human isolates available so far — they all share a common ancestor. However, does that suggest when the jump to humans occur? There are known rates of coronavirus mutations in humans and that can give some clue to how much divergence has occurred in humans and it appears that it has not diverged much at all. I wonder if this virus, like other coronaviruses, was circulating in the midst of a relatively forceful flu season and not diagnosed or noticed because many of the cases mimic influenza and other respiratory viruses. The data, based on assumed mutation rates, suggests this jumped no earlier than October 29, 2019 which would give the virus an almost 2 month head start to spread comingled in the flu season.The Makona variant of Ebola Zaire, which was the result of a single viral spillover from bats, circulated for 3 months before notice in Guinea.

If this is so, I expect case counts to rise as the virus circulates and deaths to rise as well (though at a much lower rate). Maybe this virus will become another established seasonal coronavirus with severity that is intermediate between the community acquired coronaviruses (OCV43, 220E, NL63, HKU1) and MERS and SARS? (Note that HKU1 can cause severe disease and may be an intermediate coronavirus as well)

I also believe if there is widespread community prevalence of this virus there is likely a significant severity bias in case reporting as well as in conceptualization of this viral syndrome. Imagine if you didn’t know anything about influenza and RSV and scoured adult ICUs and hospital floors. You would get a totally different picture of these diseases than if you were out in urgent care centers and PCP offices?

None of the above is meant to minimize this outbreak but my attempt to make sense of it.

If DA were here, I would ask him and know he would have an answer in a minute. It is at times like these that his giant, reasoned, prescient voice is what the world needs.