Who Is Immune to the Coronavirus?

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.

China clamping down on coronavirus research, deleted pages suggest

The Guardian

Stephanie Kirchgaessner,

Emma Graham-Harrison 

and Lily Kuo

Sat 11 Apr 2020 13.33 BST

China is cracking down on publication of academic research about the origins of the novel coronavirus, in what is likely to be part of a wider attempt to control the narrative surrounding the pandemic, documents published online by Chinese universities appear to show.

Two websites for leading Chinese universities appear to have recently published and then removed pages that reference a new policy requiring academic papers dealing with Covid-19 to undergo extra vetting before they are submitted for publication.

Research on the origins of the virus is particularly sensitive and subject to checks by government officials, the notices posted on the websites of Fudan University and the China University of Geosciences (Wuhan) said. Both the deleted pages were accessed from online caches.

Prof Steve Tsang, director of the SOAS China Institute in London, said the Chinese government had had a heavy focus on how the evolution and management of the virus is perceived since the early days of the outbreak.

“In terms of priority, controlling the narrative is more important than the public health or the economic fallout,” he said. “It doesn’t mean the economy and public health aren’t important. But the narrative is paramount.”

With the virus having infected more than a million people worldwide and caused heavy casualties particularly across Europe and the US, details about its origin and the first weeks of the pandemic – when there was a cover-up by local officials – may be considered particularly sensitive.

 “If these documents are authentic it would suggest the government really wants to control the narrative about the origins of Covid-19 very tightly,” said Tsang of the reports of new regulations.

China University of Geosciences (Wuhan) appears to have published and then deleted new requirements that academic papers dealing with the origins of the virus be approved by China’s ministry of science and technology before publication.

The university’s academic committee was expected to first go through the research “with an emphasis on checking the accuracy of the thesis, as well as whether it is suitable for publication,” the regulation said.

“When the checks have been completed, the school should report to the Ministry of Science and Technology [MOST], and it should only be published after it has [also] been checked by MOST,” it said.

Despite its name, the geosciences university announced elsewhere on its website that it was carrying out coronavirus research.

A separate document obtained by the Guardian, which could not be independently verified, appears to be from the Renmin Hospital of Wuhan University and also said publication of research into the origins of Covid-19 would need approval from the science and technology ministry

Another notice, which appears to have been published on 9 April by the school of information science and technology at Fudan University in Shanghai, called for “strict and serious” management of papers investigating the source of the outbreak.

Papers could only be submitted for publication after being approved by a special office. Email, names and phone numbers provided on the notice suggested that office was part of China’s ministry of education.

A source who alerted the Guardian to cached versions of the websites, and who spoke on the condition of anonymity, said they were concerned by what appeared to be an attempt by Chinese authorities to intervene in the independence of the scientific process.

The person said researchers submitting academic papers on other medical topics did not have to vet their work with government ministries before seeking publication.

A technical analysis of the cached websites indicated that the posts were published on verified university websites before they were removed. The Guardian could not independently verify that they reflected a new government policy.

The notices appear to be part of a broader push to manage research on the virus. The science and technology ministry said on 3 April that ongoing clinical research on the coronavirus must be reported to authorities within three days or be halted.

In March China’s president, Xi Jinping, published an essay that included “tracing the origin of the virus” on a list of national priorities. It was referenced by the science and technology ministry shortly before the universities posted their orders.

The Chinese government did not reply to a request for comment sent by the Guardian to the Chinese embassy in Washington.

While the exact origin of the pandemic is still not certain, one commonly held hypothesis is that it began following an interaction between a human and an animal at the Huanan seafood “wet market” in Wuhan.

Scientists have said the virus probably originated in bats and then passed through an intermediary animal before infecting the first human.

Scientists believe the transmission was similar to that in the 2002 outbreak of Sars. Some criticism of China has focused on why the government did not shut down wet markets after the previous outbreaks of coronaviruses.

Kevin Carrico, a senior research fellow of Chinese studies at Monash University, said he was not aware of any specific recent change to rules for academic research in China in connection to Covid-19, but the documents were generally consistent with efforts by China to control the narrative of the pandemic.

“They are seeking to transform it from a massive disaster to one where the government did everything right and gave the rest of the world time to prepare,” Carrico said.

Carrico said those efforts had been evident in communications ranging from government pronouncements at the highest level to public sentiment on social media.

“There is a desire to a degree to deny realities that are staring at us in the face … that this is a massive pandemic that originated in a place that the Chinese government really should have cleaned up after Sars,” he said.

Around a month ago senior Chinese diplomats, officials and state media all publicly encouraged speculation that the new coronavirus could have come from outside the country. The foreign ministry spokesman Zhao Lijian suggested without evidence that the US military might have brought the virus to Wuhan. 

The coming giant internal Israeli war over a nuclear Iran – A 2010 rematch

 The Jerusalem Post

A member of Iranian Border Guards wears a protective face mask

By YONAH JEREMY BOB    

A massive internal storm may be coming that the coronavirus may delay, but cannot stop.

If it does, it will pit Prime Minister Benjamin Netanyahu, Mossad Director Yossi Cohen and others against Blue and White leaders Benny Gantz and Gabi Ashkenazi, as well as IDF Chief of Staff Lt.- Gen. Aviv Kochavi, over how to deal with Iran.

According to numerous interviews by The Jerusalem Post with current and former Mossad, CIA and other national security officials in the US and Israel, a point may get closer where the Islamic Republic of Iran will escalate its levels of uranium enrichment dangerously close to levels where it could weaponize within a short period.

This will draw Netanyahu, Cohen and their camp closer to a desire to preemptively strike Iran, while Gantz, Ashkenazi, Kochavi and their camp are more likely to define the “point of no return” – after which Tehran cannot be stopped from going nuclear – as a good bit later.

This debate would echo the all-out fight between Netanyahu and Gantz and Ashkenazi in 2010 and afterwards.

During that period, the Blue and White MKs followed each other as IDF chiefs and, especially Ashkenazi, helped block an Israeli preemptive strike, along with then-Mossad chiefs Meir Dagan and Tamir Pardo.

Pardo has since confirmed that he even discussed the issue with then-attorney-general Yehuda Weinstein. He explained that he believed a Netanyahu order to move pieces in place for a near-immediate attack on Iran without full security cabinet approval was illegal and said Weinstein confirmed his position.

There are multiple narratives, with one involving confusing moves by Netanyahu and then-defense minister Ehud Barak to merely scare the world into thinking they would attack.

But the majority public narrative is that the defense establishment’s opposition blocked Netanyahu and Barak from launching an attack.

Most expert estimates already have Tehran’s time to break out for a nuclear bomb – if it chooses to do so, which all agree it has not yet – down from 12 months to between three and a half to six months.

In early March, the usually relatively Iran-friendly International Atomic Energy Agency reported that the ayatollahs already had enough low-level (between 3.67-5%) enriched uranium for a nuclear weapon – should Iran make the decision to enrich to higher levels.

Multiple intelligence sources have indicated to the Post a belief that the Islamic Republic may jump to 20% enrichment, a step it took before the 2015 Iran nuclear deal.

Some sources even speculated that Supreme Leader Ayatollah Ali Khamenei may green light a small amount of enrichment at the 60% level (uranium becomes weaponized at the 90% level) – an idea the country already played with months ago, but has not yet carried out.

But sources have indicated that top intelligence officials in favor of an earlier military option to stop Iran from getting a nuclear bomb are not looking at just one specific factor.

Rather, they are looking at the full picture of Tehran’s actions, which will indicate whether it has made the decision to go to the threshold.

According to intelligence officials who view the point of no return as an earlier point in time, they look at nuclear enrichment as a more decisive factor for interpreting Iran’s intentions than the ability to deliver a nuclear weapon.

Put differently, they believe Israel would need to act militarily once Iran has enough nuclear material for a weapon, and that it could not wait for the point at which it is confirmed that Iran can properly fire the weapon.

The rationale of these intelligence officials is that enriching uranium and working on weapons delivery issues, though separate skills to master, do not need to happen in a chronological fashion.

Instead, intelligence officials have noted to the Post that the Islamic Republic could be working through problems with delivering a nuclear warhead on its Shahab 3 missile or other missiles in parallel to its uranium enrichment.

Further, these officials said once Iran gets to within a certain proximity to enough weaponized material for a nuclear bomb, the uncertainties – which might drag out the process by some period of weeks or might be solved immediately – are too fluid. 

THERE IS a lesson from the North Korea case.

With North Korea, at some point the world was surprised by how slow it moved forward with developing nuclear weapons. However, later it shocked the world by being months ahead of what was expected. Exporting this lesson to Iran, it means the point of no return cannot wait for the clock to run out entirely.

Those intelligence officials in this camp are also keeping a careful eye on relations between the IAEA and the ayatollahs. Relations have gotten shakier since the March report, which used harsher language than usual against the regime.

In contrast, in January, Kochavi publicly laid out that he did not view Iran as a real nuclear threat until deep into 2021.

The Post has asked the IDF if Kochavi might move his calendar up by nine months since he also predicted in January that Tehran would not have enough low-enriched uranium for a bomb before December. Yet, the regime crossed that threshold already in March.

The IDF did not respond and has not issued a revised timeline.

This suggests that the IDF will not change its calendar as long as Iran is not enriching uranium to higher levels.

However, even more significantly, Kochavi explicitly treated the issues of uranium enrichment and nuclear weapons delivery as separate and chronological. He said weapons delivery pushed the nuclear threat off until deep into 2021.

It appears that this was the position of Ashkenazi and Gantz back in the 2010 era when they held Kochavi’s job.

At that point – and leading up to the 2015 nuclear deal – Iran went far beyond where it is today with nuclear enrichment, yet they were still dead set against Netanyahu and Barak’s discussion/order to attack.

Before the 2015 nuclear deal, Iran had enough low-enriched uranium for around 10 nuclear bombs and had substantial amounts of uranium enriched to the 20% level – which it has not done yet this time.

So even if Khamenei brings Iran far beyond its current uranium stock of low-enriched uranium for one weapon, and if he orders uranium enrichment at the 20% level, a rematch could mean Netanyahu’s Blue and White partners trying to hold him back from an attack.

Kochavi in the present, and Gantz, Ashkenazi, Dagan and Pardo from the past and present, in part represent an IDF mentality of needing to juggle short-term threats, like Hezbollah and Hamas, with long-term threats. They also represent an intelligence perspective beyond the IDF that even a surgical strike solely on Iran’s nuclear facilities could likely lead to a broader war with Iran and its proxies.

In contrast, Netanyahu and Cohen now, and Barak in the past, represented a mentality that the risks of Iran developing a nuclear weapon are so great (that it might use a weapon or that it could use the weapon to act more aggressively in the region) that it trumps other risks and warrants acting sooner.

This future internal war, a rematch of the 2010 era, could decide the fate of the country.

Benny Gantz on Iran

Caroline Glick accuses Dagan and Ashkenazi of blocking attack on Iran

Uncommon Knowledge: Trump, China, and the Geopolitics of a Crisis