COVID-19: Recovery & Immunity

RATHER THAN beginning my mornings with a book as usual, have been beginning them instead, with the Coronavirus COVID-19 Global Cases by the Center for Systems Science and Engineering (CSSE) at John Hopkins University (JHU) map, a far less pleasant way to begin the day, but given the current state of things, necessary. For us, being as well-informed as possible seems to help with the stress and anxiety we’ve been feeling while social distancing at home. I’ve been noticing that I seem to burst into tears much more easily lately―a story about a girl who adopted her elderly neighbours as grandparents on Humans of New York; a clip on the 6 o’clock news of apartment block residents converging on their separate balconies every night at 8:00 pm to applaud the efforts of healthcare workers in France. Everything has taken on a new and deeper meaning.

To keep sane and keep from having a complete nervous breakdown, we’re spending most of our time working and staying informed as much as possible. Here in the UK, there has been much debate about whether the government has reacted too slowly, only closing all non-essential businesses and services yesterday. According to The Washington Post, “Italy has become the flash point of the coronavirus pandemic, with a death toll of more than 6,000 and counting—the highest in the world. The staggering toll stands for now as a worst-case scenario for what happens when a country is caught unprepared. Italy’s large elderly population has exacerbated the problem. But while some unique aspects have amplified the scale, doctors and health officials say other countries should regard Italy not as an outlier or an example of missteps, but as a harrowing preview of the hardships they might soon have at hand. The disaster in Italy does not stem from gross government negligence. Rather, analysts say it is partly a consequence of the weeks between the emergence of the outbreak and the government decision to absolutely lock down the population.”

Here, the initial plan for handling the virus was based “on advice from a very small group of scientists that for a long time differed from the wider international consensus” (Buzzfeed) with use of the term “herd immunity”, and Boris Johnson speaking in a television interview that “…one of the theories is, that perhaps you could take it on the chin, take it all in one go and allow the disease, as it were, to move through the population, without taking as many draconian measures [such as cancelling public events and closing schools].” Only after there was widespread disquiet at the slow pace of the government’s response to the coronavirus was there a move toward these measures.

But perhaps it was ten days too late. According to The Guardian, data suggests that the UK is lagging behind other countries in social distancing. Only time will tell, but a cabinet minister who spoke with Buzzfeed stated, “This is going to get much, much worse, very quickly, both in terms of deaths and the economy. … It will not be long before we are getting numbers like Italy. I don’t think people realise that yet.”

As dire as that sounds, the situation has been changing rapidly day to day, and even moment to moment, and for now, in Italy for two days running, the percentage increase in the number of cases has remained at around 8%―the lowest rise in percentage terms since the contagion came to light at the end of February. Global recoveries have now passed 100,000 and the first UK patients have been enrolled in a clinical trial for possible COVID-19 treatments, and in new news today, it appears that “The coronavirus is not mutating significantly as it circulates through the human population, according to scientists who are closely studying the novel pathogen’s genetic code. That relative stability represents encouraging news for researchers hoping to create a long-lasting vaccine. All viruses evolve over time, accumulating mutations as they replicate imperfectly inside a host’s cells in tremendous numbers and then spread through a population. But the new coronavirus looks pretty much the same everywhere it has appeared, the scientists say, and there is no evidence that some strains are deadlier than others.” (The Washington Post)

With this information in mind, and with the fact that global recoveries have passed 100,000 for the first time (although it’s important to note that the virus is accelerating), let’s take a (cautious) look at recovery and immunity to COVID-19. For this, we’ve been following Nicholas A. Christakis, a physician and Sterling Professor of Social & Natural Science at Yale. The information below was compiled from Christakis’s series of tweets on the subject published on March 20, 2020 on his twitter account @NAChristakis

Let’s talk about what happens if you get COVID19 and recover. Are you immune to the disease? How long does the immunity last? And what does that mean for your life and for the public health and economy of our society?

Probably as many as 40% of humans will be exposed to COVID-19 over the next 2-3 years, judging from past pandemics. Not everyone will actually get it. Only some (probably <1.0%) of those who get it will die. The rest will recover. And, almost all of them will be immune. But we don’t know how long this immunity lasts. For some diseases (like polio or chickenpox), you are basically immune for the rest of your life. But for many others, that’s not the case. This is a complicated area in immunology.

To sort this out, we need different kind of test than what many are discussing. Most [people] are discussing rRT-PCR assays that detect whether patients actually have coronavirus RNA. But that only works for people who are currently infected since it’s detecting SARS-CoV-2 itself. Chinese scientists created tests for SARS-CoV-2 itself by early January … this article notes the USA’s lag in testing even back then.

When humans get an infection, such as with SARS-Cov-2, we make antibodies to the components of the invader, especially against proteins on the viral surface. These antibodies can neutralize the virus and also protect us from getting infected again. A key target for human antibodies against SARS-CoV-2 (such targets that our immune system attacks are known as the “antigens” of the pathogen) is the so-called “spike protein” on the virus surface. The “serological” tests that we need for the virus detect human antibodies to such viral antigens. That is, they are a test of our response to the virus rather than of the presence of the virus. Scientists have perfected such tests for decades (for example).

A first test for antibodies to SARS-CoV-2 appeared as early as February 4. Both IgM & IgG (those are two different kinds of antibodies, with IgA being a third) were low or undetectable at day 0, but increased by day 5 in nearly all patients (N=16). Scientists in Singapore followed suit with an antibody test, also in February. Many groups are racing to create such tests, which will have great commercial and clinical value. Our antibodies to the virus can be measured from ‘none’ to high levels.

Incidentally, the way we will make a vaccine is to artificially stimulate our immunity by giving just (noninfectious!) parts of the virus to people, so that they create antibodies and then fight off any real infection, if later exposed. A vaccine is a simulated infection. We are lucky that SARS-CoV-2 is very “immunogenic,” which means that our immune system finds the virus very irritating and can mount a vigorous immune response against it. Damn virus. Developing serological tests should actually be a national and international priority. For many reasons.

[The] USA has [the] opportunity to avoid mistakes with [the] lack of RNA tests for acute phase of COVID-19. We can make rapid progress and put into place distribution and insurance coverage. Test[s] should be free (we need legislation), since we all benefit from immunity & knowing who is immune. There is a lot of research on such tests at present. Dr. Krammer explains a new paper from his group in this technical thread here.

The assays for SARS-CoV-2 in this paper by @florian_krammer et al are so sensitive that they can detect the virus as early as 3 days post symptom onset. The analyses by @florian_krammer et al also show something else: it looks like humans have, as we have been expecting, not encountered this virus before. We are all “immunologically naive.” We have no natural immunity. This helps explain why the virus has spread so quickly and has become pandemic. There are few (if any) natural breakwaters in our species. We know from prior research that antibodies against viral antigens render us immune, but we do not yet know how long the immunity will last (to learn this will require follow-up time, and we are still only at the outset of the epidemic). Hence, the duration of immunity to a new coronavirus like SARS-CoV-2 is very difficult to know. We will just have to ‘wait and see’ — which is an expression that I find myself using so often with COVID-19 and that is so frustrating for all of us.

But we already can know, and do know, the early time course of immunity for COVID-19, over the first 40 days since onset of illness. “Seroconversion” in 173 patients appeared for Ab, IgM, & IgG in 11, 12, & 14 days. Presence of antibodies was <40% in first 7d & then rapidly increased to 100%, 94%, & 80% for Ab, IgM, & IgG by 15d. In contrast, viral RNA decreased from 67% before day 7 to 46% in days 15-39. We can, however, look at other coronaviruses and see what we can learn about the possible duration of immunity for COVID-19, once we are further into the epidemic and have longer follow-up. We can guess based on past science.

Here is a classic 1990 study of 15 volunteers who were deliberately infected with a different coronavirus squirted into their nose, with immunity monitored for a year. Immunity reached a maximum at 2 weeks. It had lapsed by a year later. Amazingly, 9 volunteers returned to lab to be ‘re-challenged’ by having virus squirted into their nose a second time! Although their antibody titers had declined, they still had some immunity, since only 6 of 9 became re-infected and none developed symptoms. So, that’s great! Alas, as an aside, the decline in titers also means that developing a vaccine for COVID-19 may be very challenging, similar to the reasons we do not yet have a vaccine for the common cold (but that is the topic for another thread).

Serological tests are important even in acute phase of COVID-19 because tests for virus itself could be falsely negative (for many clinical & technical reasons, eg poor technique swabbing throat). Detecting antibodies to the virus offers us another way to spot the little devil. As the epidemic proceeds, we will want to do serological tests (by drawing blood) on as many people as possible to identify people who have recovered and are highly likely to be immune. This should be a national priority.

People who are known to be immune based on such serological tests for SARS-CoV-2 are no longer infectious (they basically cannot spread the virus), and they can return to work, school, etc. This is going to be especially valuable for health care workers. But here’s the thing: once you’re immune to COVID-19, you can go about your business. Immune people can move about & help restore our economy. As number of such people rises, it will also confer “herd immunity” to our population, by blocking viral transmission, helping us all! Incidentally, if a person in a household is known to have had COVID based on the extant RNA test and is now recovered, they are a good choice of person to send out for errands, since they are also now immune.

Serological tests are also important because they help determine true denominator of people who got infected and recovered without symptoms or minimal symptoms, which is crucial for computing COVID-19 IFR (infection fatality ratio), as @mlipsitch notes here.

When we have widespread serological testing of a representative sample of people, we will be able to compute numbers of people already exposed (and naturally immunized—ie, without a vaccine) to SARS-COV-2. We might find that the IFR is much lower than we have been fearing. Eventually, we could also even extract antibodies from humans who are immune (this is called ‘serum’—and it’s like making a blood donation) and use it as a treatment for seriously ill people with COVID-19 (this treatment can cause other problems, but that’s another story).

A nice review of the biology of many possible strategies to treat COVID-19, including ‘passive antibody transfer’ from one patient to another, using serum, [can be found] here.

by Nicholas A. Christakis