Pfizer/BioNTech vaccine
Study Shows Benefits of COVID-19 Vaccines and Boosters
Posted on by Lawrence Tabak, D.D.S., Ph.D.
As colder temperatures settle in and people spend more time gathered indoors, cases of COVID-19 and other respiratory illnesses almost certainly will rise. That’s why, along with scheduling your annual flu shot, it’s now recommended that those age 5 and up should get an updated COVID-19 booster shot [1,2]. Not only will these new boosters guard against the original strain of the coronavirus that started the pandemic, they will heighten your immunity to the Omicron variant and several of the subvariants that continue to circulate in the U.S. with devastating effects.
At last count, about 14.8 million people in the U.S.—including me—have rolled up their sleeves to receive an updated booster shot [3]. It’s a good start, but it also means that most Americans aren’t fully up to date on their COVID-19 vaccines. If you or your loved ones are among them, a new study may provide some needed encouragement to make an appointment at a nearby pharmacy or clinic to get boosted [4].
A team of NIH-supported researchers found a remarkably low incidence of severe COVID-19 illness last fall, winter, and spring among more than 1.6 million veterans who’d been vaccinated and boosted. Severe illness was also quite low in individuals without immune-compromising conditions.
These latest findings, published in the journal JAMA, come from a research group led by Dan Kelly, University of California, San Francisco. He and his team conducted their study drawing on existing health data from the Veterans Health Administration (VA) within a time window of July 2021 and May 2022.
They identified 1.6 million people who’d had a primary-care visit within the last two years and were fully vaccinated for COVID-19, which included receiving a booster shot. Almost three-quarters of those identified were 65 and older. Nearly all were male, and more than 70 percent had another pre-existing health condition that put them at greater risk of becoming seriously ill from a COVID-19 infection.
Over a 24-week follow-up period for each fully vaccinated individual, 125 per 10,000 people had a breakthrough infection. That’s about 1 percent. Just 8.9 in 10,000 fully vaccinated people—less than 0.1 percent—died or were hospitalized from COVID-19 pneumonia. Drilling down deeper into the data:
• Individuals with an immune-compromising condition had a very low rate of hospitalization or death. In this group, 39.6 per 10,000 people had a serious breakthrough infection. That translates to 0.3 percent.
• For people with other preexisting health conditions, including diabetes and heart disease, hospitalization or death totaled 0.07 percent, or 6.7 per 10,000 people.
• For otherwise healthy adults aged 65 and older, the incidence of hospitalization or death was 1.9 per 10,000 people, or 0.02 percent.
• For boosted participants 65 or younger with no high-risk conditions, hospitalization or death came to less than 1 per 10,000 people. That comes to less than 0.01 percent.
It’s worth noting that these results reflect a period when the Delta and Omicron variants were circulating, and available boosters still were based solely on the original variant. Heading into this winter, the hope is that the updated “bivalent” boosters from Pfizer and Moderna will offer even broader protection as this terrible virus continues to evolve.
The Centers for Disease Control and Prevention continues to recommend that everyone stay up to date with their COVID-19 vaccines. That means all adults and kids 5 and older are encouraged to get boosted if it has been at least two months since their last COVID-19 vaccine dose. For older people and those with other health conditions, it’s even more important given their elevated risk for severe illness.
What if you’ve had a COVID-19 infection recently? Getting vaccinated or boosted a few months after you’ve had a COVID-19 infection will offer you even better protection in the future.
So, if you are among the millions of Americans who’ve been vaccinated for COVID-19 but are now due for a booster, don’t delay. Get yourself boosted to protect your own health and the health of your loved ones as the holidays approach.
References:
[1] CDC recommends the first updated COVID-19 booster. Centers for Disease Control and Prevention. September 1, 2022.
[2] CDC expands updated COVID-19 vaccines to include children ages 5 through 11. Centers for Disease Control and Prevention, October 12, 2022.
[3] COVID-19 vaccinations in the United States. Centers for Disease Control and Prevention.
[4] Incidence of severe COVID-19 illness following vaccination and booster with BNT162b2, mRNA-1273, and Ad26.COV2.S vaccines. Kelly JD, Leonard S, Hoggatt KJ, Boscardin WJ, Lum EN, Moss-Vazquez TA, Andino R, Wong JK, Byers A, Bravata DM, Tien PC, Keyhani S. JAMA. 2022 Oct 11;328(14):1427-1437.
Links:
COVID-19 Research (NIH)
Dan Kelly (University of California, San Francisco)
NIH Support: National Institute of Allergy and Infectious Diseases
How COVID-19 Immunity Holds Up Over Time
Posted on by Lawrence Tabak, D.D.S., Ph.D.
More than 215 million people in the United States are now fully vaccinated against the SARS-CoV-2 virus responsible for COVID-19 [1]. More than 40 percent—more than 94 million people—also have rolled up their sleeves for an additional, booster dose. Now, an NIH-funded study exploring how mRNA vaccines are performing over time comes as a reminder of just how important it will be to keep those COVID-19 vaccines up to date as coronavirus variants continue to circulate.
The results, published in the journal Science Translational Medicine, show that people who received two doses of either the Pfizer or Moderna COVID-19 mRNA vaccines did generate needed virus-neutralizing antibodies [2]. But levels of those antibodies dropped considerably after six months, suggesting declining immunity over time.
The data also reveal that study participants had much reduced protection against newer SARS-CoV-2 variants, including Delta and Omicron. While antibody protection remained stronger in people who’d also had a breakthrough infection, even that didn’t appear to offer much protection against infection by the Omicron variant.
The new study comes from a team led by Shan-Lu Liu at The Ohio State University, Columbus. They wanted to explore how well vaccine-acquired immune protection holds up over time, especially in light of newly arising SARS-CoV-2 variants.
This is an important issue going forward because mRNA vaccines train the immune system to produce antibodies against the spike proteins that crown the surface of the SARS-CoV-2 coronavirus. These new variants often have mutated, or slightly changed, spike proteins compared to the original one the immune system has been trained to detect, potentially dampening the immune response.
In the study, the team collected serum samples from 48 fully vaccinated health care workers at four key time points: 1) before vaccination, 2) three weeks after the first dose, 3) one month after the second dose, and 4) six months after the second dose.
They then tested the ability of antibodies in those samples to neutralize spike proteins as a correlate for how well a vaccine works to prevent infection. The spike proteins represented five major SARS-CoV-2 variants. The variants included D614G, which arose very soon after the coronavirus first was identified in Wuhan and quickly took over, as well as Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), and Omicron (B.1.1.529).
The researchers explored in the lab how neutralizing antibodies within those serum samples reacted to SARS-CoV-2 pseudoviruses representing each of the five variants. SARS-CoV-2 pseudoviruses are harmless viruses engineered, in this case, to bear coronavirus spike proteins on their surfaces. Because they don’t replicate, they are safe to study without specially designed biosafety facilities.
At any of the four time points, antibodies showed a minimal ability to neutralize the Omicron spike protein, which harbors about 30 mutations. These findings are consistent with an earlier study showing a significant decline in neutralizing antibodies against Omicron in people who’ve received the initial series of two shots, with improved neutralizing ability following an additional booster dose.
The neutralizing ability of antibodies against all other spike variants showed a dramatic decline from 1 to 6 months after the second dose. While there was a marked decline over time after both vaccines, samples from health care workers who’d received the Moderna vaccine showed about twice the neutralizing ability of those who’d received the Pfizer vaccine. The data also suggests greater immune protection in fully vaccinated healthcare workers who’d had a breakthrough infection with SARS-CoV-2.
In addition to recommending full vaccination for all eligible individuals, the Centers for Disease Control and Prevention (CDC) now recommends everyone 12 years and up should get a booster dose of either the Pfizer or Moderna vaccines at least five months after completing the primary series of two shots [3]. Those who’ve received the Johnson & Johnson vaccine should get a booster at least two months after receiving the initial dose.
While plenty of questions about the durability of COVID-19 immunity over time remain, it’s clear that the rapid deployment of multiple vaccines over the course of this pandemic already has saved many lives and kept many more people out of the hospital. As the Omicron threat subsides and we start to look forward to better days ahead, it will remain critical for researchers and policymakers to continually evaluate and revise vaccination strategies and recommendations, to keep our defenses up as this virus continues to evolve.
References:
[1] COVID-19 vaccinations in the United States. Centers for Disease Control and Prevention. February 27, 2022.
[2] Neutralizing antibody responses elicited by SARS-CoV-2 mRNA vaccination wane over time and are boosted by breakthrough infection. Evans JP, Zeng C, Carlin C, Lozanski G, Saif LJ, Oltz EM, Gumina RJ, Liu SL. Sci Transl Med. 2022 Feb 15:eabn8057.
[3] COVID-19 vaccine booster shots. Centers for Disease Control and Prevention. Feb 2, 2022.
Links:
COVID-19 Research (NIH)
Shan-Lu Liu (The Ohio State University, Columbus)
NIH Support: National Institute of Allergy and Infectious Diseases; National Cancer Institute; National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development
Latest on Omicron Variant and COVID-19 Vaccine Protection
Posted on by Dr. Francis Collins
There’s been great concern about the new Omicron variant of SARS-CoV-2, the coronavirus that causes COVID-19. A major reason is Omicron has accumulated over 50 mutations, including about 30 in the spike protein, the part of the coronavirus that mRNA vaccines teach our immune systems to attack. All of these genetic changes raise the possibility that Omicron could cause breakthrough infections in people who’ve already received a Pfizer or Moderna mRNA vaccine.
So, what does the science show? The first data to emerge present somewhat encouraging results. While our existing mRNA vaccines still offer some protection against Omicron, there appears to be a significant decline in neutralizing antibodies against this variant in people who have received two shots of an mRNA vaccine.
However, initial results of studies conducted both in the lab and in the real world show that people who get a booster shot, or third dose of vaccine, may be better protected. Though these data are preliminary, they suggest that getting a booster will help protect people already vaccinated from breakthrough or possible severe infections with Omicron during the winter months.
Though Omicron was discovered in South Africa only last month, researchers have been working around the clock to learn more about this variant. Last week brought the first wave of scientific data on Omicron, including interesting work from a research team led by Alex Sigal, Africa Health Research Institute, Durban, South Africa [1].
In lab studies working with live Omicron virus, the researchers showed that this variant still relies on the ACE2 receptor to infect human lung cells. That’s really good news. It means that the therapeutic tools already developed, including vaccines, should generally remain useful for combatting this new variant.
Sigal and colleagues also tested the ability of antibodies in the plasma from 12 fully vaccinated individuals to neutralize Omicron. Six of the individuals had no history of COVID-19. The other six had been infected with the original variant in the first wave of infections in South Africa.
As expected, the samples showed very strong neutralization against the original SARS-CoV-2 variant. However, antibodies from people who’d been previously vaccinated with the two-dose Pfizer vaccine took a significant hit against Omicron, showing about a 40-fold decline in neutralizing ability.
This escape from immunity wasn’t complete. Indeed, blood samples from five individuals showed relatively good antibody levels against Omicron. All five had previously been infected with SARS-CoV-2 in addition to being vaccinated. These findings add to evidence on the value of full vaccination for protecting against reinfections in people who’ve had COVID-19 previously.
Also of great interest were the first results of the Pfizer study, which the company made available in a news release [2]. Pfizer researchers also conducted laboratory studies to test the neutralizing ability of blood samples from 19 individuals one month after a second shot compared to 20 others one month after a booster shot.
These studies showed that the neutralizing ability of samples from those who’d received two shots had a more than 25-fold decline relative to the original virus. Together with the South Africa data, it suggests that the two-dose series may not be enough to protect against breakthrough infections with the Omicron variant.
In much more encouraging news, their studies went on to show that a booster dose of the Pfizer vaccine raised antibody levels against Omicron to a level comparable to the two-dose regimen against the original variant (as shown in the figure above). While efforts already are underway to develop an Omicron-specific COVID-19 vaccine, these findings suggest that it’s already possible to get good protection against this new variant by getting a booster shot.
Very recently, real-world data from the United Kingdom, where Omicron cases are rising rapidly, are providing additional evidence for how boosters can help. In a preprint [3], Andrews et. al showed the effectiveness of two shots of Pfizer mRNA vaccine trended down after four months to about 40 percent. That’s not great, but note that 40 percent is far better than zero. So, clearly there is some protection provided.
Most impressively (as shown in the figure from Andrews N, et al.) a booster substantially raised that vaccine effectiveness to about 80 percent. That’s not quite as high as for Delta, but certainly an encouraging result. Once again, these data show that boosting the immune system after a pause produces enhanced immunity against new viral variants, even though the booster was designed from the original virus. Your immune system is awfully clever. You get both quantitative and qualitative benefits.
It’s also worth noting that the Omicron variant mostly doesn’t have mutations in portions of its genome that are the targets of other aspects of vaccine-induced immunity, including T cells. These cells are part of the body’s second line of defense and are generally harder for viruses to escape. While T cells can’t prevent infection, they help protect against more severe illness and death.
It’s important to note that scientists around the world are also closely monitoring Omicron’s severity While this variant appears to be highly transmissible, and it is still early for rigorous conclusions, the initial research indicates this variant may actually produce milder illness than Delta, which is currently the dominant strain in the United States.
But there’s still a tremendous amount of research to be done that could change how we view Omicron. This research will take time and patience.
What won’t change, though, is that vaccines are the best way to protect yourself and others against COVID-19. (And these recent data provide an even-stronger reason to get a booster now if you are eligible.) Wearing a mask, especially in public indoor settings, offers good protection against the spread of all SARS-CoV-2 variants. If you’ve got symptoms or think you may have been exposed, get tested and stay home if you get a positive result. As we await more answers, it’s as important as ever to use all the tools available to keep yourself, your loved ones, and your community happy and healthy this holiday season.
References:
[1] SARS-CoV-2 Omicron has extensive but incomplete escape of Pfizer BNT162b2 elicited neutralization and requires ACE2 for infection. Sandile C, et al. Sandile C, et al. medRxiv preprint. December 9, 2021.
[2] Pfizer and BioNTech provide update on Omicron variant. Pfizer. December 8, 2021.
[3] Effectiveness of COVID-19 vaccines against the Omicron (B.1.1.529) variant of concern. Andrews N, et al. KHub.net preprint. December 10, 2021.
Links:
COVID-19 Research (NIH)
Sigal Lab (Africa Health Research Institute, Durban, South Africa)
Accelerating COVID-19 Vaccine Testing with ‘Correlates of Protection’
Posted on by Dr. Francis Collins
With Omicron now on so many people’s minds, public health officials and virologists around the world are laser focused on tracking the spread of this concerning SARS-CoV-2 variant and using every possible means to determine the effectiveness of our COVID-19 vaccines against it. Ultimately, the answer will depend on what happens in the real world. But it will also help to have a ready laboratory means for gauging how well a vaccine works, without having to wait many months for the results in the field.
With this latter idea in mind, I’m happy to share results of an NIH-funded effort to understand the immune responses associated with vaccine-acquired protection against SARS-CoV-2 [1]. The findings, based on the analysis of blood samples from more than 1,000 people who received the Moderna mRNA vaccine, show that antibody levels do correlate, albeit somewhat imperfectly, with how well a vaccine works to prevent infection.
Such measures of immunity, known as “correlates of protection,” have potential to support the approval of new or updated vaccines more rapidly. They’re also useful to show how well a vaccine will work in groups that weren’t represented in a vaccine’s initial testing, such as children, pregnant women, and those with certain health conditions.
The latest study, published in the journal Science, comes from a team of researchers led by Peter Gilbert, Fred Hutchinson Cancer Research Center, Seattle; David Montefiori, Duke University, Durham, NC; and Adrian McDermott, NIH’s Vaccine Research Center, National Institute of Allergy and Infectious Diseases.
The team started with existing data from the Coronavirus Efficacy (COVE) trial. This phase 3 study, conducted in 30,000 U.S. adults, found the Moderna vaccine was safe and about 94 percent effective in protecting people from symptomatic infection with SARS-CoV-2 [2].
The researchers wanted to understand the underlying immune responses that afforded that impressive level of COVID-19 protection. They also sought to develop a means to measure those responses in the lab and quickly show how well a vaccine works.
To learn more, Gilbert’s team conducted tests on blood samples from COVE participants at the time of their second vaccine dose and again four weeks later. Two of the tests measured concentrations of binding antibodies (bAbs) that latch onto spike proteins that adorn the coronavirus surface. Two others measured the concentration of more broadly protective neutralizing antibodies (nAbs), which block SARS-CoV-2 from infecting human cells via ACE2 receptors found on their surfaces.
Each of the four tests showed antibody levels that were consistently higher in vaccine recipients who did not develop COVID-19 than in those who did. That is consistent with expectations. But these data also allowed the researchers to identify the specific antibody levels associated with various levels of protection from disease.
For those with the highest antibody levels, the vaccine offered an estimated 98 percent protection. Those with levels about 1,000 times lower still were well protected, but their vaccine efficacy was reduced to about 78 percent.
Based on any of the antibodies tested, the estimated COVID-19 risk was about 10 times lower for vaccine recipients with antibodies in the top 10 percent of values compared to those with antibodies that weren’t detectable. Overall, the findings suggest that tests for antibody levels can be applied to make predictions about an mRNA vaccine’s efficacy and may be used to guide modifications to the current vaccine regimen.
To understand the significance of this finding, consider that for a two-dose vaccine like Moderna or Pfizer, a trial using such correlates of protection might generate sufficient data in as little as two months [3]. As a result, such a trial might show whether a vaccine was meeting its benchmarks in 3 to 5 months. By comparison, even a rapid clinical trial done the standard way would take at least seven months to complete. Importantly also, trials relying on such correlates of protection require many fewer participants.
Since all four tests performed equally well, the researchers say it’s conceivable that a single antibody assay might be sufficient to predict how effective a vaccine will be in a clinical trial. Of course, such trials would require subsequent real-world studies to verify that the predicted vaccine efficacy matches actual immune protection.
It should be noted that the Food and Drug Administration (FDA) would need to approve the use of such correlates of protection before their adoption in any vaccine trial. But, to date, the totality of evidence on neutralizing antibody responses as correlates of protection—for which this COVE trial data is a major contributor—is impressive.
Neutralizing antibody levels are also now being considered for use in future coronavirus vaccine trials. Indeed, for the EUA of Pfizer’s mRNA vaccine for 5-to-11-year-olds, the FDA accepted pre-specified success criteria based on neutralizing antibody responses in this age group being as good as those observed in 16- to 25-year-olds [4].
Antibody levels also have been taken into consideration for decisions about booster shots. However, it’s important to note that antibody levels are not precise enough to help in deciding whether or not any particular individual needs a COVID-19 booster. Those recommendations are based on how much time has passed since the original immunization.
Getting a booster is a really good idea heading into the holidays. The Delta variant remains very much the dominant strain in the U.S., and we need to slow its spread. Most experts think the vaccines and boosters will also provide some protection against the Omicron variant—though the evidence we need is still a week or two away. The Centers for Disease Control and Prevention (CDC) recommends a COVID-19 booster for everyone ages 18 and up at least six months after your second dose of mRNA vaccine or two months after receiving the single dose of the Johnson & Johnson vaccine [5]. You may choose to get the same vaccine or a different one. And, there is a place near you that is offering the shot.
References:
[1] Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical trial.
Gilbert PB, Montefiori DC, McDermott AB, Fong Y, Benkeser D, Deng W, Zhou H, Houchens CR, Martins K, Jayashankar L, Castellino F, Flach B, Lin BC, O’Connell S, McDanal C, Eaton A, Sarzotti-Kelsoe M, Lu Y, Yu C, Borate B, van der Laan LWP, Hejazi NS, Huynh C, Miller J, El Sahly HM, Baden LR, Baron M, De La Cruz L, Gay C, Kalams S, Kelley CF, Andrasik MP, Kublin JG, Corey L, Neuzil KM, Carpp LN, Pajon R, Follmann D, Donis RO, Koup RA; Immune Assays Team§; Moderna, Inc. Team§; Coronavirus Vaccine Prevention Network (CoVPN)/Coronavirus Efficacy (COVE) Team§; United States Government (USG)/CoVPN Biostatistics Team§. Science. 2021 Nov 23:eab3435.
[2] Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, Diemert D, Spector SA, Rouphael N, Creech CB, McGettigan J, Khetan S, Segall N, Solis J, Brosz A, Fierro C, Schwartz H, Neuzil K, Corey L, Gilbert P, Janes H, Follmann D, Marovich M, Mascola J, Polakowski L, Ledgerwood J, Graham BS, Bennett H, Pajon R, Knightly C, Leav B, Deng W, Zhou H, Han S, Ivarsson M, Miller J, Zaks T; COVE Study Group. N Engl J Med. 2021 Feb 4;384(5):403-416.
[3] A government-led effort to identify correlates of protection for COVID-19 vaccines. Koup RA, Donis RO, Gilbert PB, Li AW, Shah NA, Houchens CR. Nat Med. 2021 Sep;27(9):1493-1494.
[4] Evaluation of the BNT162b2 Covid-19 vaccine in children 5 to 11 years of age. Walter EB, Talaat KR, Sabharwal C, Gurtman A, Lockhart S, Paulsen GC, Barnett ED, Muñoz FM, Maldonado Y, Pahud BA, Domachowske JB, Simões EAF, Sarwar UN, Kitchin N, Cunliffe L, Rojo P, Kuchar E, Rämet M, Munjal I, Perez JL, Frenck RW Jr, Lagkadinou E, Swanson KA, Ma H, Xu X, Koury K, Mather S, Belanger TJ, Cooper D, Türeci Ö, Dormitzer PR, Şahin U, Jansen KU, Gruber WC; C4591007 Clinical Trial Group. N Engl J Med. 2021 Nov 9:NEJMoa2116298.
[5] COVID-19 vaccine booster shots. Centers for Disease Control and Prevention. Nov 29, 2021.
Links:
COVID-19 Research (NIH)
Combat COVID (U.S. Department of Health and Human Services)
Peter Gilbert (Fred Hutchison Cancer Research Center)
David Montefiori (Duke University, Durham, NC)
Adrian McDermott (National Institute of Allergy and Infectious Diseases/NIH)
NIH Support: National Institute of Allergy and Infectious Diseases
Feeling Grateful This Thanksgiving for Biomedical Research
Posted on by Dr. Francis Collins
Yes, we can all agree that 2021 has been a tough year. But despite all that, Thanksgiving is the right time to stop and count our many blessings. My list starts with my loving wife Diane and family, all of whom have been sources of encouragement in these trying times. But also high up on the list this Thanksgiving is my extreme gratitude to the scientific community for all the research progress that has been made over the past 23 months to combat the pandemic and return our lives ever closer to normal.
Last year, we were busy learning how to celebrate a virtual Thanksgiving. This year, most of us are feeling encouraged about holding face-to-face gatherings once again—but carefully!—and coordinating which dishes to prepare for the annual feast.
The COVID-19 vaccines, developed by science in record time and with impressive safety and effectiveness, have made this possible. The almost 230 million Americans who have chosen to receive at least one dose of a COVID-19 vaccine have taken a critical step to protect themselves and others. They have made this season a much safer one for themselves and those around them than a year ago. That includes almost all adults ages 65 and up. While vaccination rates aren’t yet as high as they need to be in younger age groups, about 70 percent of Americans ages 12 and up are now fully vaccinated.
But with evidence that the effectiveness of the vaccines can wane over time and with the continued threat of the Delta variant, I was happy to see the recent approval by both FDA and CDC that all adults 18 and over are now eligible to receive a booster. That is, provided you are now more than 6 months past your initial immunization with the Moderna or Pfizer or 2 months past your immunization with the Johnson & Johnson vaccine. I recently got my Moderna booster and I’m glad for that additional protection. Don’t wait—the booster is the best way to defend against a possible winter surge.
Children age 5 and up are also now eligible to get the Pfizer vaccine, a development that I know brought a sense of relief and gratitude for many parents with school-aged children at home. It will take a little time for full vaccination of this age group. But more than 2.5 million young kids around the country already have rolled up their sleeves and have some immunity against COVID-19. These children are on track to be fully vaccinated before Christmas.
I’m also extremely grateful for all the progress that’s been made in treating COVID-19. Developing new treatments typically takes many years, if not decades. But NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative, a public-private partnership involving 20 biopharmaceutical companies, academic experts, and multiple federal agencies, has helped lead the way to this rapid progress.
We’ve seen successes in the use of monoclonal antibodies and in the repurposing of existing drugs, such as blood thinning treatments, to keep folks hospitalized with COVID-19 from becoming severely ill and needing some form of organ support. Now it looks as though our hopes for safe and effective oral antiviral medicines to reduce the risk of severe illness in individuals just diagnosed with COVID-19 could soon be realized, too.
To combat COVID-19, rapid and readily accessible testing also is key, and NIH’s Rapid Acceleration of Diagnostics (RADx®) initiative continues to speed innovation in COVID-19 testing. RADx® also recently launched a simple online calculator tool to help individuals make critical decisions about when to get a test [1]. Meanwhile, a new initiative called Say Yes! COVID Test (SYCT) is exploring how best to implement home-testing programs in our communities.
More research progress is on the way. But, until the pandemic is history, please remember to stay safe this holiday season. The best way to do so is to get fully vaccinated [2]. As I noted above, most adults who got vaccinated earlier this year are now eligible for a booster shot to ensure they remain well protected. Go to vaccines.gov to find the site closest to you that can provide the shot.
The best way to protect young children who aren’t yet eligible or fully vaccinated and others who may be at higher risk is by making sure you and others around them are vaccinated. It’s still strongly recommended to wear a well-fitting mask over your nose and mouth when in public indoor settings, especially if there’s considerable spread of COVID-19 in your community.
If you are gathering with multiple households or people from different parts of the country, consider getting tested for COVID-19 in advance and take extra precautions before traveling. By taking full advantage of all the many scientific advances we’ve made over the last year, we can now feel good about celebrating together again this holiday season. Happy Thanksgiving!
References:
[1] When to Test offers free online tool to help individuals make informed COVID-19 testing decisions. National Institutes of Health. November 3, 2021.
[2] Safer ways to celebrate holidays. Centers for Disease Control and Prevention. October 15, 2021.
Links:
COVID-19 Research (NIH)
Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (NIH)
Rapid Acceleration of Diagnostics (RADx®) (NIH)
When To Test (Consortia for Improving Medicine with Innovation & Technology, Boston)
Israeli Study Shows How COVID-19 Immunity Wanes over Time
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 [1]. 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.
Reference:
[1] 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.
Links:
COVID-19 Research (NIH)
COVID-19 Vaccine Booster Shots (Centers for Disease Control and Prevention)
Frequently Asked Influenza (Flu) Questions: 2021-2022 Season (CDC)
Breakthrough Infections Occur in Those with Lower Antibody Levels, Israeli Study Shows
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 [1]. 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 [2]. 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.
References:
[1] 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.
[2] Rates of COVID-19 cases and deaths by vaccination status, COVID Data Tracker, Centers for Disease and Prevention. Accessed October 25, 2021.
Links:
COVID-19 Research (NIH)
Sheba Medical Center (Ramat Gan, Israel)
The Latest on COVID-19 Boosters
Posted on by Dr. Francis Collins
More than 180 million Americans, including more than 80 percent of people over age 65, are fully vaccinated against the SARS-CoV-2 virus responsible for COVID-19. There’s no question that full vaccination is the best way to protect yourself against this devastating virus and reduce your chances of developing severe or long-lasting illness if you do get sick. But, to stay ahead of this terrible virus, important questions do remain. A big one right now is: How soon will booster shots be needed and for whom?
The answers to this question will continue to evolve as more high-quality data become available. But here’s what we know right now for the Pfizer-BioNTech booster. Late last week, Dr. Rochelle Walensky, the Director of the Centers for Disease Control and Prevention (CDC), recommended that:
- Those 65 years and older and residents in long-term care settings should receive a booster shot at least 6 months after being fully vaccinated with the Pfizer-BioNTech vaccine,
- People aged 50–64 years with underlying medical conditions should receive a booster shot at least 6 months after being fully vaccinated with the Pfizer-BioNTech vaccine,
- Individuals aged 18–49 years with underlying medical conditions may receive a booster shot at least 6 months after getting fully vaccinated with their Pfizer-BioNTech vaccine, based on their individual benefits and risks.
- Frontline workers who received the Pfizer-BioNTech vaccine may receive a booster. This group includes anyone age 18 through 64 whose frequent institutional or occupational exposure to SARS-CoV-2 puts them at high risk of COVID-19. [1]
Taken together, these CDC recommendations are in line with those issued two days earlier by the Food and Drug Administration (FDA) [2].
Some of the most-compelling data that was under review came from an Israeli study, published recently in the New England Journal of Medicine, that explored the benefit of booster shots for older people [3]. Israel, with a population of around 9 million, has a national health system and one of the world’s highest COVID-19 vaccination rates. That country’s vaccination campaign, based solely on Pfizer-BioNTech, was organized early in 2021, and so its experience is about three months ahead of ours here in the U.S. These features, plus some of the world’s largest integrated health record databases, have made Israel an important source of early data on how the Pfizer-BioNTech mRNA vaccine can be expected to work in the real world over time.
Earlier this year, Israeli public health officials noted evidence for an increased number of breakthrough infections, some of which were severe. So, at the end of July 2021, Israel approved the administration of third doses, or “boosters,” of the Pfizer-BioNTech vaccine for people ages 60 and up who had received their second dose at least five months before.
To find out how well these booster shots worked to bolster immune protection against COVID-19, researchers looked to more than 1.1 million fully vaccinated people who were at least 60 years old. They compared the rate of confirmed COVID-19 infection and severe illness from the end of July to the end of August among people who’d received a booster at least 12 days earlier with those who hadn’t gotten boosters.
Nearly 13,500 older individuals who’d been fully vaccinated before March 2021, got a breakthrough infection during the two months of study. Importantly, the rate of confirmed infection in the group that got boosters was 10 times lower on average than in the group that didn’t get boosters. The data on severe illness looked even better. Of course, there could be other factors at play that weren’t accounted for in the study, but the findings certainly suggest that a third Pfizer shot is safe and effective for older people.
Though the Israeli studies on booster shots are a little ahead of the international pack, we are starting to see results from the research underway in the U.S. Last week, for example, Johnson & Johnson announced new data in support of boosters to improve and extend immune protection in those who received its single-dose COVID-19 vaccine [4]. For people who received the Moderna mRNA vaccine, the company has already submitted its data to the FDA for booster authorization. A decision is expected soon.
As the critical evidence on boosters continues to emerge, the most important way to avoid another winter surge of COVID-19 is to follow all public health recommendations. Most importantly, that includes getting fully vaccinated if you haven’t already, and encouraging others around you to do the same. If you’re currently eligible for a booster shot, they are available at 80,000 locations across the nation, and can help you stay healthy and well for the coming holiday season.
For others eager to do everything possible to protect themselves, their families, and their communities against this terrible virus—but who are not yet eligible for a booster—sit tight for now. The data on booster shots are still coming in for folks like me who were immunized with the Moderna or Johnson & Johnson vaccines. It’s likely that the FDA and CDC will widen their recommendations in the coming weeks.
In the meantime, the Delta variant is still out there and circulating. That makes it critical to maintain vigilance. Wear a mask in indoor spaces, keep a physical distance from others, and remember to wash your hands frequently. We are all really tired of COVID-19, but patience is still required as we learn more about how best to stay ahead of this virus.
References:
[1] CDC statement on ACIP booster recommendations. Centers for Disease Control and Prevention news release. September 24, 2021
[2] FDA authorizes booster dose of Pfizer-BioNTech COVID-19 vaccine for certain populations. Food and Drug Administration news release. September 22, 2021
[3] Protection of BNT162b2 vaccine booster against Covid-19 in Israel. Bar-On YM, Goldberg Y, Mandel M, Bodenheimer O, Freedman L, Kalkstein N, Mizrahi B, Alroy-Preis S, Ash N, Milo R, Huppert A. N Engl J Med. 2021 Sep 15.
[4] Johnson & Johnson announces real-world evidence and Phase 3 data confirming strong and long-lasting protection of single-shot COVID-19 vaccine in the U.S. Johnson & Johnson. September 21, 2021.
Links:
COVID-19 Research (NIH)
Breakthrough Infections in Vaccinated People Less Likely to Cause ‘Long COVID’
Posted on by Dr. Francis Collins
There’s no question that vaccines are making a tremendous difference in protecting individuals and whole communities against infection and severe illness from SARS-CoV-2, the coronavirus that causes COVID-19. And now, there’s yet another reason to get the vaccine: in the event of a breakthrough infection, people who are fully vaccinated also are substantially less likely to develop Long COVID Syndrome, which causes brain fog, muscle pain, fatigue, and a constellation of other debilitating symptoms that can last for months after recovery from an initial infection.
These important findings published in The Lancet Infectious Diseases are the latest from the COVID Symptom Study [1]. This study allows everyday citizens in the United Kingdom to download a smartphone app and self-report data on their infection, symptoms, and vaccination status over a long period of time.
Previously, the study found that 1 in 20 people in the U.K. who got COVID-19 battled Long COVID symptoms for eight weeks or more. But this work was done before vaccines were widely available. What about the risk among those who got COVID-19 for the first time as a breakthrough infection after receiving a double dose of any of the three COVID-19 vaccines (Pfizer, Moderna, AstraZeneca) authorized for use in the U.K.?
To answer that question, Claire Steves, King’s College, London, and colleagues looked to frequent users of the COVID Symptom Study app on their smartphones. In its new work, Steves’ team was interested in analyzing data submitted by folks who’d logged their symptoms, test results, and vaccination status between December 9, 2020, and July 4, 2021. The team found there were more than 1.2 million adults who’d received a first dose of vaccine and nearly 1 million who were fully vaccinated during this period.
The data show that only 0.2 percent of those who were fully vaccinated later tested positive for COVID-19. While accounting for differences in age, sex, and other risk factors, the researchers found that fully vaccinated individuals who developed breakthrough infections were about half (49 percent) as likely as unvaccinated people to report symptoms of Long COVID Syndrome lasting at least four weeks after infection.
The most common symptoms were similar in vaccinated and unvaccinated adults with COVID-19, and included loss of smell, cough, fever, headaches, and fatigue. However, all of these symptoms were milder and less frequently reported among the vaccinated as compared to the unvaccinated.
Vaccinated people who became infected were also more likely than the unvaccinated to be asymptomatic. And, if they did develop symptoms, they were half as likely to report multiple symptoms in the first week of illness. Another vaccination benefit was that people with a breakthrough infection were about a third as likely to report any severe symptoms. They also were more than 70 percent less likely to require hospitalization.
We still have a lot to learn about Long COVID, and, to get the answers, NIH has launched the RECOVER Initiative. The initiative will study tens of thousands of COVID-19 survivors to understand why many individuals don’t recover as quickly as expected, and what might be the cause, prevention, and treatment for Long COVID.
In the meantime, these latest findings offer the encouraging news that help is already here in the form of vaccines, which provide a very effective way to protect against COVID-19 and greatly reduce the odds of Long COVID if you do get sick. So, if you haven’t done so already, make a plan to protect your own health and help end this pandemic by getting yourself fully vaccinated. Vaccines are free and available near to you—just go to vaccines.gov or text your zip code to 438829.
Reference:
[1] Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study. Antonelli M, Penfold RS, Merino J, Sudre CH, Molteni E, Berry S, Canas LS, Graham MS, Klaser K, Modat M, Murray B, Kerfoot E, Chen L, Deng J, Österdahl MF, Cheetham NJ, Drew DA, Nguyen LH, Pujol JC, Hu C, Selvachandran S, Polidori L, May A, Wolf J, Chan AT, Hammers A, Duncan EL, Spector TD, Ourselin S, Steves CJ. Lancet Infect Dis. 2021 Sep 1:S1473-3099(21)00460-6.
Links:
COVID-19 Research (NIH)
Claire Steves (King’s College London, United Kingdom)
mRNA Vaccines May Pack More Persistent Punch Against COVID-19 Than Thought
Posted on by Dr. Francis Collins
Many people, including me, have experienced a sense of gratitude and relief after receiving the new COVID-19 mRNA vaccines. But all of us are also wondering how long the vaccines will remain protective against SARS-CoV-2, the coronavirus responsible for COVID-19.
Earlier this year, clinical trials of the Moderna and Pfizer-BioNTech vaccines indicated that both immunizations appeared to protect for at least six months. Now, a study in the journal Nature provides some hopeful news that these mRNA vaccines may be protective even longer [1].
In the new study, researchers monitored key immune cells in the lymph nodes of a group of people who received both doses of the Pfizer-BioNTech mRNA vaccine. The work consistently found hallmarks of a strong, persistent immune response against SARS-CoV-2 that could be protective for years to come.
Though more research is needed, the findings add evidence that people who received mRNA COVID-19 vaccines may not need an additional “booster” shot for quite some time, unless SARS-CoV-2 evolves into new forms, or variants, that can evade this vaccine-induced immunity. That’s why it remains so critical that more Americans get vaccinated not only to protect themselves and their loved ones, but to help stop the virus’s spread in their communities and thereby reduce its ability to mutate.
The new study was conducted by an NIH-supported research team led by Jackson Turner, Jane O’Halloran, Rachel Presti, and Ali Ellebedy at Washington University School of Medicine, St. Louis. That work builds upon the group’s previous findings that people who survived COVID-19 had immune cells residing in their bone marrow for at least eight months after the infection that could recognize SARS-CoV-2 [2]. The researchers wanted to see if similar, persistent immunity existed in people who hadn’t come down with COVID-19 but who were immunized with an mRNA vaccine.
To find out, Ellebedy and team recruited 14 healthy adults who were scheduled to receive both doses of the Pfizer-BioNTech vaccine. Three weeks after their first dose of vaccine, the volunteers underwent a lymph node biopsy, primarily from nodes in the armpit. Similar biopsies were repeated at four, five, seven, and 15 weeks after the first vaccine dose.
The lymph nodes are where the human immune system establishes so-called germinal centers, which function as “training camps” that teach immature immune cells to recognize new disease threats and attack them with acquired efficiency. In this case, the “threat” is the spike protein of SARS-COV-2 encoded by the vaccine.
By the 15-week mark, all of the participants sampled continued to have active germinal centers in their lymph nodes. These centers produced an army of cells trained to remember the spike protein, along with other types of cells, including antibody-producing plasmablasts, that were locked and loaded to neutralize this key protein. In fact, Ellebedy noted that even after the study ended at 15 weeks, he and his team continued to find no signs of germinal center activity slowing down in the lymph nodes of the vaccinated volunteers.
Ellebedy said the immune response observed in his team’s study appears so robust and persistent that he thinks that it could last for years. The researcher based his assessment on the fact that germinal center reactions that persist for several months or longer usually indicate an extremely vigorous immune response that culminates in the production of large numbers of long-lasting immune cells, called memory B cells. Some memory B cells can survive for years or even decades, which gives them the capacity to respond multiple times to the same infectious agent.
This study raises some really important issues for which we still don’t have complete answers: What is the most reliable correlate of immunity from COVID-19 vaccines? Are circulating spike protein antibodies (the easiest to measure) the best indicator? Do we need to know what’s happening in the lymph nodes? What about the T cells that are responsible for cell-mediated immunity?
If you follow the news, you may have seen a bit of a dust-up in the last week on this topic. Pfizer announced the need for a booster shot has become more apparent, based on serum antibodies. Meanwhile, the Food and Drug Administration and Centers for Disease Control and Prevention said such a conclusion would be premature, since vaccine protection looks really good right now, including for the delta variant that has all of us concerned.
We’ve still got a lot more to learn about the immunity generated by the mRNA vaccines. But this study—one of the first in humans to provide direct evidence of germinal center activity after mRNA vaccination—is a good place to continue the discussion.
References:
[1] SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses. Turner JS, O’Halloran JA, Kalaidina E, Kim W, Schmitz AJ, Zhou JQ, Lei T, Thapa M, Chen RE, Case JB, Amanat F, Rauseo AM, Haile A, Xie X, Klebert MK, Suessen T, Middleton WD, Shi PY, Krammer F, Teefey SA, Diamond MS, Presti RM, Ellebedy AH. Nature. 2021 Jun 28. [Online ahead of print]
[2] SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans. Turner JS, Kim W, Kalaidina E, Goss CW, Rauseo AM, Schmitz AJ, Hansen L, Haile A, Klebert MK, Pusic I, O’Halloran JA, Presti RM, Ellebedy AH. Nature. 2021 May 24. [Online ahead of print]
Links:
COVID-19 Research (NIH)
Ellebedy Lab (Washington University, St. Louis)
NIH Support: National Institute of Allergy and Infectious Diseases; National Center for Advancing Translational Sciences
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