Posted on by Dr. Francis Collins
About 70,000 people in the United States are diagnosed with COVID-19 each and every day. It’s clear that these new cases are being driven by the more-infectious Delta variant of SARS-CoV-2, the novel coronavirus that causes COVID-19. But why does the Delta variant spread more easily than other viral variants from one person to the next?
Now, an NIH-funded team has discovered at least part of Delta’s secret, and it’s not all attributable to those widely studied mutations in the spike protein that links up to human cells through the ACE2 receptor. It turns out that a specific mutation found within the N protein coding region of the Delta genome also enables the virus to pack more of its RNA code into the infected host cell. As a result, there is increased production of fully functional new viral particles, which can go on to infect someone else.
This finding, published in the journal Science , comes from the lab of Nobel laureate Jennifer Doudna at the Howard Hughes Medical Institute, the Gladstone Institutes, San Francisco, and the Innovative Genomics Institute at the University of California, Berkeley. Co-leading the team was Melanie Ott, Gladstone Institutes.
The Doudna and Ott teams have developed an exciting new tool to study variants of the coronavirus. It’s a lab construct called a virus-like particle (VLP). These specially made VLPs have all the structural proteins of SARS-CoV-2 (shown above), but they contain no genetic material. Consequently, they are non-infectious replicas of the real virus that can be studied safely in any lab. Scientists don’t have to reserve time in labs equipped with heightened levels of biosafety, as is required when working with whole virus.
The VLPs also allow researchers to explore changes found in the coronavirus’s other essential proteins, not just the spike protein on its surface. In fact, all of the SARS-CoV-2 variants of concern, as defined by the World Health Organization (WHO), carry at least one mutation within the same stretch of seven amino acids in a viral protein known as the nucleocapsid (N protein). This protein, which hasn’t been widely studied, is required for the virus to make more of itself. It is also involved in the virus’s ability to package and release infectious RNA.
In the Science paper, Doudna and colleagues took a closer look at the N protein. They did so by developing a special system that used VLPs to package and deliver viral RNA messages into human cells.
Here’s how it works: The VLPs include all four of SARS-CoV-2’s structural proteins, including the spike and N proteins. In addition, they contain the RNA sequence that allows the virus to recognize its genetic material within the cell, so that it can be packaged into the next generation of viral particles.
Though the particles look just like SARS-CoV-2 from the outside, they lack the vast majority of the viral genome on the inside. But they do have one other key component: a snippet of RNA that makes cells invaded by VLPs glow. In fact, the more RNA messages a VLP delivers, the brighter the cells will glow. It allowed the researchers to spot successful invasions, while also quantifying the amount of RNA a particular VLP packed into a cell.
The researchers then produced SARS-CoV-2 VLPs including four mutations that are universally found within the N proteins of more transmissible variants of concern. That’s when they discovered those variants produced and delivered 10 times more RNA messages into cells.
The increased RNA also fits with what has been observed in people infected with the Delta variant. They produce about 10 times more virus in their nose and throat compared to people infected with the older variants.
But did those findings match what happens in the real virus? To find out, the researchers and their colleagues tested the N protein mutation found in the Delta variant in a high-level biosafety lab. And, indeed, their studies showed that the mutated virus within infected human lung cells produced about 50 times more infectious virus compared to the original SARS-CoV-2 variant.
The findings suggest that the N protein could be an important new target for effective COVID-19 therapeutics, and that tracking newly emerging mutations in the N protein might also be important for identifying new viral variants of concern. This new system is a powerful tool, and one that can also be used for exploring how newly arising variants in the future might affect the course of this terrible pandemic.
 Rapid assessment of SARS-CoV-2 evolved variants using virus-like particles. Syed AM, Taha TY, Tabata T, Chen IP, Ciling A, Khalid MM, Sreekumar B, Chen PY, Hayashi JM, Soczek KM, Ott M, Doudna JA. Science. 2021 Nov 4:eabl6184.
COVID-19 Research (NIH)
NIH Support: National Institute of Allergy and Infectious Diseases
Posted on by Dr. Francis Collins
The winter holidays are approaching, and among the many things to be grateful for this year is that nearly 200 million Americans are fully vaccinated for COVID-19. That will make it safer to spend time with friends and family, though everyone should remain vigilant just to be on the safe side. Though relatively uncommon, breakthrough infections are possible. That’s why the Centers for Disease Control and Prevention (CDC) recommends booster shots for several at-risk groups, including folks 65 years and older, those with underlying medical conditions, and people whose occupations place them at high risk of exposure.
One of the main studies providing the evidence for CDC’s recommendation was recently published in the New England Journal of Medicine . It found that vaccine-induced immunity, while still quite protective against infection and severe illness from COVID-19, can wane after several months.
The study is yet another highly informative report from Israel, where public health officials launched a particularly vigorous national vaccination campaign in December 2020. More than half of adult Israelis received two doses of the Pfizer vaccine within the first three months of the campaign. By May 2021, Israel had extremely small numbers of confirmed COVID-19 cases—just a few dozen per day.
But the numbers crept back up in June 2021. The rise also included a substantial number of breakthrough infections in vaccinated individuals. The vast majority of those cases in June—98 percent—were caused by the emerging Delta variant.
Researchers led by Yair Goldberg, Technion-Israel Institute of Technology, Haifa, wondered whether this resurgence of COVID-19 could be fully explained by the rise of the more infectious Delta variant. Or, they wondered, did the waning of immunity over time also play a role?
To find out, the researchers looked to over 4.7 million fully vaccinated Israeli adults, more than 13,000 of whom had breakthrough infections from July 11 to 31, 2021 with SARS-CoV-2. The researchers looked for an association between the rate of confirmed infections and the time that had passed since vaccination. Without any significant waning of immunity, one shouldn’t see any difference in infection rates among people who were fully vaccinated at the earliest opportunity versus those vaccinated later.
The results were clear: the rate of confirmed COVID-19 infection revealed a slow but steady waning of immunity over time. Among individuals 60 years or older who were fully vaccinated last January, the number of confirmed breakthrough infections was 3.3 per 1,000 people during the three weeks of the study. Those who were vaccinated in February and March had lower infection rates of 2.2 per 1,000 and 1.7 per 1,000, respectively. The data revealed a similar pattern in those aged 40 to 59 and those aged 16 to 39.
An important question is whether these breakthrough infections were serious enough to require hospitalization. While such cases were much less common, more than 400 of those with confirmed COVID-19 breakthroughs went on to develop severe illness. And, again, the data show a similar pattern of waning immunity. The rate of severe COVID-19 among adults 60 years of age or older who were fully vaccinated in January was 0.34 cases per 1,000 persons. The rate of severe illness dropped to 0.26 cases per 1,000 among those vaccinated in February and 0.15 cases per 1,000 for those vaccinated in March. The researchers report that the number of severe COVID-19 cases among the younger fully vaccinated groups were too small to draw any conclusions.
While the Delta variant surely has played a role in the resurgence of COVID-19 in recent months, these findings suggest that waning immunity also is an important factor. Understanding these dynamics is essential for making critical policy decisions. In fact, these data were a key factor in the decision by the Israeli Ministry of Health in July 2021 to approve administration of COVID-19 booster shots for individuals who’d been vaccinated at least 5 months before.
Back in the U.S., if you were among those who got your vaccine on the early side—good for you. If it’s been more than six months since your original shots, and if you are in one of the risk groups, you should consider a COVID-19 booster shot to remain optimally protected in the months ahead. I’ll be getting my Moderna booster this week. While you’re at it, consider getting your annual flu shot taken care of, too. The CDC guidelines state that it’s perfectly OK to get your COVID-19 and flu shots at the same time.
 Waning immunity after the BNT162b2 vaccine in Israel. Goldberg Y, Mandel M, Bar-On YM, Bodenheimer O, Freedman L, Haas EJ, Milo R, Alroy-Preis S, Ash N, Huppert A. N Engl J Med. 2021 Oct 27.
COVID-19 Research (NIH)
COVID-19 Vaccine Booster Shots (Centers for Disease Control and Prevention)
Posted on by Dr. Francis Collins
To see how COVID-19 vaccines are working in the real world, Israel has provided particularly compelling data. The fact that Israel is relatively small, keeps comprehensive medical records, and has a high vaccination rate with a single vaccine (Pfizer) has contributed to its robust data collection. Now, a new Israeli study offers some insight into those relatively uncommon breakthrough infections. It confirms that breakthrough cases, as might be expected, arise most often in individuals with lower levels of neutralizing antibodies.
The findings reported in The New England Journal of Medicine focused on nearly 1,500 of about 11,500 fully vaccinated health care workers at Sheba Medical Center, Ramat Gan, Israel . All had received two doses of the Pfizer mRNA vaccine. But, from December 19, 2020 to April 28, 2021, they were tested for a breakthrough infection due to a known exposure to someone with COVID-19 or possible symptoms of the disease.
Just 39 confirmed breakthrough cases were found, indicating a breakthrough infection rate of just 0.4 percent. That’s consistent with rates reported in previous studies. Most in the Israeli study who tested positive for COVID-19 had mild or no symptoms and none required hospitalization.
In the new study, researchers led by Gili Regev-Yochay at Sheba Medical Center’s Infection Control and Prevention Unit, characterized as many breakthrough infections as possible among the health care workers. Almost half of the infections involved members of the hospital nursing staff. But breakthrough cases also were found in hospital administration, maintenance workers, doctors, and other health professionals.
The average age of someone with a breakthrough infection was 42, and it’s notable that only one person was known to have a weakened immune system. The most common symptoms were respiratory congestion, muscle aches (myalgia), and loss of smell or taste. Most didn’t develop a fever. At six weeks after diagnosis, 19 percent reported having symptoms of Long COVID syndrome, including prolonged loss of smell, persistent cough, weakness, and fatigue. About a quarter stayed home from work for longer than the required 10 days, and one had yet to return to work at six weeks.
For 22 of the 39 people with a breakthrough infection, the researchers had results of neutralizing antibody tests from the week leading up to their positive COVID-19 test result. To look for patterns in the antibody data, they matched those individuals to 104 uninfected people for whom they also had antibody test results. These data showed that those with a breakthrough infection had consistently lower levels of neutralizing antibodies circulating in their bloodstream to SARS-CoV-2, the coronavirus that causes COVID-19. In general, higher levels of neutralizing antibodies are associated with greater protection and lower infectivity—though other aspects of the immune system (memory B cells and cell-mediated immunity) also contribute.
Importantly, in all cases for which there were relevant data, the source of the breakthrough infection was thought to be an unvaccinated person. In fact, more than half of those who developed a breakthrough infection appeared to have become infected from an unvaccinated member of their own household.
Other cases were suspected to arise from exposure to an unvaccinated coworker or patient. Contact tracing found no evidence that any of the 39 health care workers with a breakthrough infection passed it on to anyone else.
The findings add to evidence that full vaccination and associated immunity offer good protection against SARS-CoV-2 infection and severe illness. Understanding how SARS-CoV-2 immunity changes over time is key for charting the course of this pandemic and making important decisions about COVID-19 vaccine boosters.
Many questions remain. For instance, it’s not clear from the study whether lower neutralizing antibodies in those with breakthrough cases reflect waning immunity or, for reasons we don’t yet understand, those individuals may have had a more limited immune response to the vaccine. Also, this study was conducted before the Delta variant became dominant in Israel (and now in the whole world).
Overall, these findings provide more reassurance that these vaccines are extremely effective. Breakthrough infections, while they can and do occur, are a relatively uncommon event. Here in the U.S., the Centers for Disease Control and Prevention (CDC) has recently estimated that infection is six times less likely for vaccinated than unvaccinated persons . That those with immunity tend to have mild or no symptoms if they do develop a breakthrough case, however, is a reminder that these cases could easily be missed, and they could put vulnerable populations at greater risk. It’s yet another reason for all those who can to get themselves vaccinated as soon as possible or consider a booster shot when they become eligible.
 Covid-19 breakthrough infections in vaccinated health care workers. Bergwerk M, Gonen T, Lustig Y, Amit S, Lipsitch M, Cohen C, Mandelboim M, Levin EG, Rubin C, Indenbaum V, Tal I, Zavitan M, Zuckerman N, Bar-Chaim A, Kreiss Y, Regev-Yochay G. N Engl J Med. 2021 Oct 14;385(16):1474-1484.
 Rates of COVID-19 cases and deaths by vaccination status, COVID Data Tracker, Centers for Disease and Prevention. Accessed October 25, 2021.
COVID-19 Research (NIH)
Sheba Medical Center (Ramat Gan, Israel)