About this
question, too, decisions with great consequences are being made, as they must
be, based on only glimmers of data.
By Marc Lipsitch
Mr.
Lipsitch is an epidemiologist and infectious disease specialist.
·
April 13, 2020
Among the many
uncertainties that remain about Covid-19 is how the human immune system
responds to infection and what that means for the spread of the disease.
Immunity after any infection can range from lifelong and complete to nearly
nonexistent. So far, however, only the first glimmers of data are available
about immunity to SARS-CoV-2, the coronavirus that causes Covid-19.
What can scientists, and the decision makers who rely on science to
inform policies, do in such a situation? The best approach is to construct a
conceptual model — a set of assumptions about how immunity might work — based
on current knowledge of the immune system and information about related
viruses, and then identify how each aspect of that model might be wrong, how
one would know and what the implications would be. Next, scientists should set
out to work to improve this understanding with observation and experiment.
The ideal scenario — once infected, a person is completely immune for
life — is correct for a number of infections. The Danish physician Peter Panum
famously figured this out for measles when he visited the Faroe Islands (between Scotland and
Iceland) during an outbreak in 1846 and found that residents over 65 who had
been alive during a previous outbreak in 1781 were protected. This striking
observation helped launch the fields of immunology and epidemiology — and ever since,
as in many other disciplines, the scientific community has learned that often
things are more complicated.
One example of “more complicated” is immunity to coronaviruses, a large group of viruses that sometimes
jump from animal hosts to humans: SARS-CoV-2 is the third major coronavirus
epidemic to affect humans in recent times, after the SARS outbreak of 2002-3
and the MERS outbreak that started in 2012
Much of our understanding of coronavirus immunity comes not from SARS or
MERS, which have infected comparatively small numbers of people, but from the
coronaviruses that spread every year causing respiratory infections ranging
from a common cold to pneumonia. In two separate studies, researchers infected
human volunteers with a seasonal coronavirus and about a year later inoculated
them with the same or a similar virus to observe whether they had acquired
immunity.
In the first study, researchers selected 18 volunteers who developed colds
after they were inoculated — or “challenged,” as the term goes — with one
strain of coronavirus in 1977 or 1978. Six of the subjects were re-challenged a
year later with the same strain, and none was infected, presumably thanks to
protection acquired with their immune response to the first infection. The
other 12 volunteers were exposed to a slightly different strain of coronavirus
a year later, and their protection to that was only partial.
In another
study published in 1990, 15 volunteers were inoculated
with a coronavirus; 10 were infected. Fourteen returned for another inoculation
with the same strain a year later: They displayed less severe symptoms and
their bodies produced less of the virus than after the initial challenge,
especially those who had shown a strong immune response the first time around.
No such human-challenge experiments have been
conducted to study immunity to SARS and MERS. But measurements of antibodies in
the blood of people who have survived those infections suggest that these
defenses persist for some time: two years for SARS, according to
one study, and almost three years for MERS, according to
another one. However, the neutralizing ability of these antibodies —
a measure of how well they inhibit virus replication — was already declining
during the study periods.
These studies form the basis for an educated
guess at what might happen with Covid-19 patients. After being infected with
SARS-CoV-2, most individuals will have an immune response, some better than
others. That response, it may be assumed, will offer some protection over the
medium term — at least a year — and then its effectiveness might decline.
Other evidence supports this model. A recent
peer-reviewed study led by a team from Erasmus University, in the Netherlands,
published data from 12 patients showing that they had developed antibodies
after infection with SARS-CoV-2. Several of my
colleagues and students and I have
statistically analyzed thousands of
seasonal coronavirus cases in the United States and used a mathematical model
to infer that immunity over a year or so is likely for the two seasonal
coronaviruses most closely related to SARS-CoV-2 — an indication perhaps of how
immunity to SARS-CoV-2 itself might also behave.
If it is true that infection creates immunity
in most or all individuals and that the protection lasts a year or more, then
the infection of increasing numbers of people in any given population will lead
to the buildup of so-called herd immunity. As more and more
people become immune to the virus, an infected individual has less and less
chance of coming into contact with a person susceptible to
infection. Eventually, herd immunity becomes pervasive enough that an infected
person on average infects less than one other person; at that point, the number
of cases starts to go down. If herd immunity is widespread enough, then even in
the absence of measures designed to slow transmission, the virus will be
contained — at least until immunity wanes or enough new people susceptible to
infection are born.
At the moment, cases of Covid-19 have been
undercounted because of limited testing — perhaps by a factor of 10 in some places, like Italy as of late last month. If
the undercounting is around this level in other countries as well, then a
majority of the population in much (if not all) of the world still is
susceptible to infection, and herd immunity is a minor phenomenon right now.
The long-term control of the virus depends on getting a majority of people to
become immune, through infection and recovery or through vaccination — how
large a majority depends on yet other parameters of the infection that remain
unknown.
One concern has to do with the
possibility of reinfection. South Korea’s
Centers for Disease Control and Prevention recently reported that 91 patients
who had been infected with SARS-CoV-2 and then tested negative for the virus later tested
positive again. If some of these cases were indeed reinfections, they would
cast doubt on the strength of the immunity the patients had developed.
An alternative
possibility, which many scientists think is more
likely, is that these patients had a false negative test in the
middle of an ongoing infection, or that the infection had temporarily subsided
and then re-emerged. South Korea’s C.D.C. is now working to assess the merit of
all these explanations. As with other diseases for which it can be difficult to
distinguish a new infection from a new flare-up of an old infection — like tuberculosis — the issue might be resolved by comparing the viral
genome sequence from the first and the second periods of infection.
For now, it is reasonable to assume that only a
minority of the world’s population is immune to SARS-CoV-2, even in hard-hit
areas. How could this tentative picture evolve as better data come in? Early
hints suggest that it could change in either direction.
It is possible that many more cases of Covid-19
have occurred than have been reported, even after accounting for limited
testing. One recent study (not yet peer-reviewed) suggests that rather than, say,
10 times the number of detected cases, the United States may really have more
like 100, or even 1,000, times the official number. This estimate is an
indirect inference from statistical correlations. In emergencies, such indirect
assessments can be early evidence of an important finding — or statistical
flukes. But if this one is correct, then herd immunity to SARS-CoV-2 could be
building faster than the commonly reported figures suggest.
Then again, another recent study (also
not yet peer-reviewed) suggests that not every case of infection may be
contributing to herd immunity. Of 175 Chinese patients with mild symptoms of
Covid-19, 70 percent developed strong antibody responses, but about 25 percent
developed a low response and about 5 percent developed no detectable response
at all. Mild illness, in other words, might not always build up protection.
Similarly, it will be important to study the immune responses of people with
asymptomatic cases of SARS-CoV-2 infection to determine whether symptoms, and
their severity, predict whether a person becomes immune.
The balance between these uncertainties will
become clearer when more serologic surveys, or blood tests for antibodies, are
conducted on large numbers of people. Such studies are beginning and should show results soon. Of course, much will
depend on how sensitive and specific the various tests are: how well they spot
SARS-CoV-2 antibodies when those are present and if they can avoid spurious
signals from antibodies to related viruses.
Even more challenging will be understanding what
an immune response means for an individual’s risk of getting reinfected and
their contagiousness to others. Based on the volunteer experiments with
seasonal coronaviruses and the antibody-persistence studies for SARS and MERS, one
might expect a strong immune response to SARS-CoV-2 to protect completely
against reinfection and a weaker one to protect against severe infection and so
still slow the virus’s spread.
But designing valid epidemiologic studies to
figure all of this out is not easy — many scientists, including several teams
of which I’m a part — are working on the issue right now. One difficulty is
that people with a prior infection might differ from people who haven’t yet
been infected in many other ways that could alter their future risk of
infection. Parsing the role of prior exposure from other risk factors is an
example of the classic problem epidemiologists call “confounding” — and it is made maddeningly harder today by the
fast-changing conditions of the still-spreading SARS-CoV-2 pandemic.
And yet getting a handle on this fast is
extremely important: not only to estimate the extent of herd immunity, but also
to figure out whether some people can re-enter society safely, without becoming
infected again or serving as a vector, and spreading the virus to others.
Central to this effort will be figuring out how long protection lasts.
With time, other aspects of immunity will become
clearer as well. Experimental and statistical evidence suggests that infection with one coronavirus
can offer some degree of immunity against distinct but related coronaviruses.
Whether some people are at greater or lesser risk of infection with SARS-CoV-2
because of a prior history of exposure to coronaviruses is an open question.
And
then there is the question of immune enhancement:
Through a variety of mechanisms, immunity to a coronavirus can in some
instances exacerbate an infection rather than prevent or mitigate it. This
troublesome phenomenon is best known in another group of viruses, the
flaviviruses, and may explain why administering a vaccine against dengue fever,
a flavivirus infection, can sometimes make the disease worse.
Such mechanisms are still being studied for
coronaviruses, but concern that they might be at play is one of the obstacles
that have slowed the development of experimental vaccines against SARS and MERS. Guarding against
enhancement will also be one of the biggest challenges facing scientists trying
to develop vaccines for Covid-19. The good news is that research on SARS and
MERS has begun to
clarify how enhancement works, suggesting ways
around it, and an
extraordinary range of efforts is underway
to find a vaccine for Covid-19, using multiple approaches.
More science on almost every aspect of this new
virus is needed, but in this pandemic, as with previous ones, decisions with great consequences must be made before
definitive data are in. Given this urgency, the traditional scientific method —
formulating informed hypotheses and testing them by experiments and careful
epidemiology — is hyper-accelerated. Given the public’s attention, that work is
unusually on display. In these difficult circumstances, I can only hope that
this article will seem out of date very shortly — as much more is soon
discovered about the coronavirus than is known right now.
Marc Lipsitch (@mlipsitch) is a professor in
the Departments of Epidemiology and Immunology and Infectious Diseases at
Harvard T.H. Chan School of Public Health, where he also directs the Center for
Communicable Disease Dynamics.
