Tag Archives: #vaccine

AstraZeneca Vaccine Found Effective for Elderly in Hard-hit Brazil Facing COVID-19 Gamma Variant (Medicine)

The AstraZeneca vaccine, which is being widely used in Brazil and elsewhere in response to an epidemic wave of the SARS-CoV-2 Gamma variant, affords significant protection to the elderly when the vaccine’s full two-dose schedule is completed.

New research by the Yale School of Public Health and a host of Brazilian and international scientists analyzed how adults aged 60 years old and older in the state of Sao Paulo, Brazil, responded to either just one dose of the vaccine or the full two-dose regimen during extensive transmission of the Gamma variant (also known as P.1). This variant has caused widespread sickness and death since it emerged in Brazil last year and has since spread to other countries in South American and beyond.

“These findings have major implications for policy in many countries that have spaced out vaccination and especially those in South America that are undergoing large Gamma associated epidemics.” said Julio Croda, adjunct associate professor at the Yale School of Public Health, a researcher at the Oswaldo Cruz Foundation in Brazil, and the study’s principal investigator. Known as ChOxD1, the vaccine is used worldwide for COVID-19.

The study results are posted on MedRxiv as a preprint paper.

The team conducted the case control study between January 17 and July 2, 2021, analyzing COVID-19 outcomes among 61,164 people who received either one of the vaccine, two doses or no vaccine doses at all. The Brazilian government initiated its vaccination campaign in January with the ChOxAd1 vaccine, using a three-month dose-spacing strategy in order to vaccinate as many people as possible while faced with a limited vaccine supply. This strategy has been endorsed by the World Health Organization.

These findings have major implications for policy in many countries.Julio Croda

The researchers found that a single dose of the vaccine among the elderly conferred protection against COVID-19, but its effectiveness was modest. One dose had an overall effectiveness of 33% against symptomatic illness and reduced hospitalizations by 55% and deaths by 61%.

In contrast, a second dose of the AstraZeneca vaccine was found to provide significantly higher protection. A complete two-dose regimen provided an overall effectiveness of 78% against COVID-19 and reduced hospitalizations by 88% and deaths by 94%.

“The good news is that the ChAdOx1 vaccine was highly effective in protecting the elderly during an epidemic where the Gamma variant caused more than 80% of the cases” said Albert Ko, the Raj and Indra Nooyi Professor of Public Health at the Yale School of Public Health and the study’s co-principal investigator. “However, unlike the experience with ChAdOx1 in other settings, two doses are needed to reach optimal levels of protection in this vulnerable population and in the setting of extensive Gamma variant transmission.”

The findings have significant implications for Brazil as well as other countries in South America, which have been particularly hard hit by the pandemic and need to prioritize vaccine supply given current shortages on the continent.

The study was performed by the VEBRA-COVID consortium, which includes researchers from Brazil and international partners, which include Oswaldo Cruz Foundation, Federal University of Mato Grosso do Sul, Nacional University of Brasilia, Barcelona Institute for Global Health, University of Florida, Stanford University, Health Secretary of São Paulo state, the Pan-American Health Organization and the Yale School of Public Health.

Featured image: Gamma Variant © Photo by Dreamstime


Reference: Otavio T. Ranzani, Matt D.T. Hitchings, Murilo Dorion, Tatiana Lang D’Agostini, Regiane Cardoso de Paula, Olivia Ferreira Pereira de Paula, Edlaine Faria de Moura Villela, Mario Sergio Scaramuzzini Torres, Silvano Barbosa de Oliveira, Wade Schulz, Maria Almiron, Rodrigo Said, Roberto Dias de Oliveira, Patricia Vieira da Silva, Wildo Navegantes de Araújo, Jean Carlo Gorinchteyn, Jason R. Andrews, Derek A.T. Cummings, Albert I. Ko, Julio Croda, “Effectiveness of the CoronaVac vaccine in the elderly population during a Gamma variant-associated epidemic of COVID-19 in Brazil: A test-negative case-control study”, medRxiv 2021.05.19.21257472; doi: https://doi.org/10.1101/2021.05.19.21257472


Provided by Yale School of Public Health

Longer Interval Between The First & Second Pfizer Vaccine Boosts Antibody Levels And ‘Helper’ T Cells (Medicine)

A new study carried out in collaboration with the University of Birmingham shows both short and long dosing schedules of the Pfizer COVID-19 vaccine generate strong antibody and T cell immune responses.

The study, led by the University of Oxford, in collaboration with the Universities of Birmingham, Newcastle, Liverpool, Sheffield, and supported by the UK Coronavirus Immunology Consortium, is one of the most comprehensive studies into the immune response generated by the Pfizer COVID-19 vaccine to date.

It found T cell levels are well-maintained and antibody levels are higher following a longer interval between the first and second dose of the Pfizer COVID-19 vaccine, despite a significant drop in antibody levels between doses. Importantly, worldwide studies are showing that both the short and long dosing schedules lead to strong real-world protection against COVID-19, emphasising the importance of having a second dose of the vaccine.

The Protective Immunity from T cells to COVID-19 in Health workers study (PITCH) examined how antibody and T cell levels change over time following either a ‘short’ (3–4 weeks, average of 24 days) or ‘long’ (6–14 weeks, average of 70 days) interval between the first and second dose of the Pfizer COVID-19 vaccine. Of the 503 healthcare workers recruited to the study, 223 (44%) had previously had COVID-19.

Key findings:

  • For the longer dosing interval, antibody levels fell noticeably between the first and second dose when tested in the lab. In particular, neutralising antibody levels against the Delta variant were poorly induced after a single dose, and not maintained during the interval before the second dose. T cells were well-maintained between the first and second dose.
  • Following two vaccine doses, neutralising antibody levels were twice as high after the longer dosing interval compared with the shorter dosing interval.
  • After two doses, overall T cell levels were 1.6 times lower after the long compared with the short dosing schedule.  However, after the longer dosing interval, a higher proportion of T cells present were ‘helper’ T cells, which are important for long-term immune memory and helping generate antibodies to prevent infection.
  • The longer dosing interval resulted in higher neutralising antibody levels, after the second dose, against the Delta variant and all other Variants of Concern tested.

Regardless of the dosing schedule, the study found levels of antibodies and T cells varied significantly from person to person, which may depend on genetics, underlying health conditions, and past exposure to COVID-19 and other viruses. This underlies the importance of everyone getting two doses of the COVID-19 vaccine to maximise their own protection, particularly against Variants of Concern. Follow up of this cohort 6 and 12 months after vaccination is needed to investigate longer term immune response, as well as whether it translates to lower or less severe infection rates.

The study results are being published as a pre-print on ‘Cell Press Sneak Peak’ and have therefore not yet been peer reviewed.

Vaccines Minister Nadhim Zahawi said: “The findings from this latest PITCH study are hugely significant not just for the UK but for the world, helping us better understand the mechanics behind our immune response to COVID-19 and the importance of getting both doses of the vaccine.
“As we raced to offer a vaccine to all adults, we took the JCVI’s advice to shorten the dosing interval from 12 to 8 weeks to help protect more people against the Delta variant. This latest study provides further evidence that this interval results in a strong immune response and supports our decision.
“I urge every adult to get both doses of the vaccine protect yourself and those around you and we are looking to offer millions of the most vulnerable a booster jab from September to ensure this protection is maintained.”

Professor Paul Moss, Principal Investigator of the UK Coronavirus Immunology Consortium and Professor of Haematology at the University of Birmingham, said: “This is an important study that reveals how changing the interval between doses of the COVID-19 vaccine has a significant effect on the immune response generated. It also demonstrates the benefit of a team science approach that brings researchers together to understand key questions on the immunology of COVID-19. The UK Coronavirus Immunology Consortium has been incredibly successful in fostering new partnerships like this.”

Alex Richter, Professor in Clinical Immunology at the University of Birmingham, said: “Real world data demonstrates the Pfizer COVID-19 vaccine is effective at reducing levels of serious disease, hospitalisation and death. There is benefit after one dose but two doses provides a much more robust response. Understanding the underlying immune response generated by different dosing schedules will help maximise future protection, tackle new Variants of Concern and prevent reinfections.”

Dr Rebecca Payne, study author from Newcastle University, said: “Our study is one of the most comprehensive assessments of the immune response to SARS-CoV-2 following two doses of the Pfizer vaccine. We found an interesting pattern in the levels of immune cells present. Our study provides reassuring evidence that both dosing schedules generate robust immune responses against SARS-CoV-2 after two doses. For the longer schedule, the antibody levels dropped off between first and second dose, which included the loss of any neutralising effect against the Delta variant. However, T cell responses were consistent, indicating they may contribute to important protection against SARS-CoV-2 during this time. After the second dose on the longer dosing schedule, antibody levels surpassed those seen at the same time point after a shorter dosing interval. Although T cell levels were comparatively lower, the profile of T cells present suggested more support of immune memory and antibody generation. We now need to carry out more follow up studies to understand the full clinical significance of our findings.”

Professor Susanna Dunachie, PITCH study lead from University of Oxford, said: “We know that the Pfizer COVID-19 vaccine is very effective at preventing serious disease, even after one dose, but we don’t yet understand what the exact immune response is that underlies this effect. Our study aimed to shine a light on the different type of immune cells involved to help us better understand the potential mechanisms of protection, particularly against new Variants of Concern. It is clear from our findings that to maximise your individual protection, it is very important to get two doses of the COVID vaccine when offered.

“This work is the result of a big team effort. The study would not have been possible without collaboration between the researchers across all five universities. It has allowed us to bring clinical cohorts together and conduct one of the most in-depth analyses of the immune response to a COVID-19 vaccine yet.”

This study formed part of the PITCH Study (Protective Immunity from T-cells in Halthcare workers), which was funded by the UK’s Department of Health and Social Care. A contribution was also made from the UK Coronavirus Immunology Consortium (funded by UK Research and Innovation and the National Institute for Health Research).


Reference: Payne et al. 2021. Sustained T cell immunity, protection and boosting using extended dosing intervals of BNT162b2 mRNA vaccine.


Provided by University of Birmingham

Study Links Vaccine Immune Response to Age (Medicine)

New OHSU laboratory research highlights importance of increasing vaccination to protect older vaccinated adults

Older people appear to have fewer antibodies against the novel coronavirus, a new laboratory study from Oregon Health & Science University suggests.

Antibodies are blood proteins that are made by the immune system to protect against infection. They are known to be key players in protection against SARS-CoV-2 infection.

The study published today in the Journal of the American Medical Association.

Head shot of Fikadu Tafesse, Ph.D, a smiling, bearded Black man
Fikadu Tafesse, Ph.D. © OHSU

“Our older populations are potentially more susceptible to the variants even if they are vaccinated,” said senior author Fikadu Tafesse, Ph.D., assistant professor of molecular microbiology and immunology in the OHSU School of Medicine.

Tafesse and colleagues emphasized that even though they measured diminished antibody response in older people, the vaccine still appeared to be effective enough to prevent infection and severe illness in most people of all ages.

“The good news is that our vaccines are really strong,” Tafesse said.

However, with vaccine uptake slowing in Oregon and across United States, researchers say their findings underscore the importance of promoting vaccinations in local communities.

Vaccinations reduce the spread of the virus and new and potentially more transmissible variants, especially for older people who appear to be more susceptible to breakthrough infections.

“The more people get vaccinated, the less the virus circulates,” Tafesse said. “Older people aren’t entirely safe just because they’re vaccinated; the people around them really need to be vaccinated as well. At the end of the day, this study really means that everybody needs to be vaccinated to protect the community.”

Researchers measured the immune response in the blood of 50 people two weeks after their second dose of the Pfizer vaccine against COVID-19. They grouped participants into age groups and then exposed their blood serum in test tubes to the original “wild-type” SARS-CoV-2 virus and the P.1 variant (also known as gamma) that originated in Brazil.

The youngest group – all in their 20s – had a nearly seven-fold increase in antibody response compared with the oldest group of people between 70 and 82 years of age. In fact, the laboratory results reflected a clear linear progression from youngest to oldest: The younger a participant, the more robust the antibody response.

“Older people might be more susceptible to variants than younger individuals,” Tafesse said.

Head shot of Marcel Curlin, M.D., a white man with curly hair.
Marcel Curlin, M.D. © OHSU

The findings highlight the importance of vaccinating older people as well as others who may be more vulnerable to COVID-19, said co-author Marcel Curlin, M.D., associate professor of medicine (infectious diseases) in the OHSU School of Medicine.

“The vaccine still produces strong immune responses compared with natural infection in most older individuals, even if they are lower than their younger counterparts,” Curlin said. “Vaccination in this group may make the difference between serious and mild disease, and likely reduces the chances of transmitting SARS-CoV-2 to another person.”

The research was supported in part by an unrestricted grant from the M.J. Murdock Charitable Trust; the National Institutes of Health grant R01AI145835 and training grant T32AI747225; and OHSU Innovative IDEA grant 1018784.

Featured image: New laboratory research from OHSU suggests that older people have diminished levels of antibodies compared to younger people after vaccination. (Getty Images)


Provided by OHSU

Why Second Dose Of COVID-19 Vaccine Shouldn’t Be Skipped? (Medicine)

Scientists scrutinized Pfizer vaccine recipients’ blood samples to learn exactly what effects the vaccine exerts on the body’s immune system.

The second dose of a COVID-19 vaccine induces a powerful boost to a part of the immune system that provides broad antiviral protection, according to a study led by investigators at the Stanford University School of Medicine.

The finding strongly supports the view that the second shot should not be skipped.

“Despite their outstanding efficacy, little is known about how exactly RNA vaccines work,” said Bali Pulendran, PhD, professor of pathology and of microbiology and immunology. “So we probed the immune response induced by one of them in exquisite detail.”

The study, published July 12 in Nature, was designed to find out exactly what effects the vaccine, marketed by Pfizer Inc., has on the numerous components of the immune response. 

The researchers analyzed blood samples from individuals inoculated with the vaccine. They counted antibodies, measured levels of immune-signaling proteins and characterized the expression of every single gene in the genome of 242,479 separate immune cells’ type and status.

“The world’s attention has recently been fixed on COVID-19 vaccines, particularly on the new RNA vaccines,” said Pulendran, the Violetta L. Horton Professor II. 

He shares senior authorship of the study with Kari Nadeau, MD, PhD, the Naddisy Foundation Professor of Pediatric Food, Allergy, Immunology, and Asthma and professor of pediatrics, and Purvesh Khatri, PhD, associate professor of biomedical informatics and of biomedical data science. The study’s lead authors are Prabhu Arunachalam, PhD, a senior research scientist in Pulendran’s lab; medical student Madeleine Scott, PhD, a former graduate student in Khatri’s lab; and Thomas Hagan, PhD, a former postdoctoral scholar in Pulendran’s Stanford lab and now an assistant professor at the Yerkes National Primate Research Center in Atlanta.

Uncharted territory

“This is the first time RNA vaccines have ever been given to humans, and we have no clue as to how they do what they do: offer 95% protection against COVID-19,” said Pulendran.

Traditionally, the chief immunological basis for approval of new vaccines has been their ability to induce neutralizing antibodies: individualized proteins, created by immune cells called B cells, that can tack themselves to a virus and block it from infecting cells. 

“Antibodies are easy to measure,” Pulendran said. “But the immune system is much more complicated than that. Antibodies alone don’t come close to fully reflecting its complexity and potential range of protection.”

Pulendran and his colleagues assessed goings-on among all the immune cell types influenced by the vaccine: their numbers, their activation levels, the genes they express and the proteins and metabolites they manufacture and secrete upon inoculation.

One key immune-system component examined by Pulendran and his colleagues was T cells: search-and-destroy immune cells that don’t attach themselves to viral particles as antibodies do but rather probe the body’s tissues for cells bearing telltale signs of viral infections. On finding them, they tear those cells up. 

In addition, the innate immune system, an assortment of first-responder cells, is now understood to be of immense importance. It’s the body’s sixth sense, Pulendran said, whose constituent cells are the first to become aware of a pathogen’s presence. Although they’re not good at distinguishing among separate pathogens, they secrete “starting gun” signaling proteins that launch the response of the adaptive immune system — the B and T cells that attack specific viral or bacterial species or strains. During the week or so it takes for the adaptive immune system to rev up, innate immune cells perform the mission-critical task of holding incipient infections at bay by gobbling up — or firing noxious substances, albeit somewhat indiscriminately, at — whatever looks like a pathogen to them.

A different type of vaccine

The Pfizer vaccine, like the one made by Moderna Inc., works quite differently from the classic vaccines composed of live or dead pathogens, individual proteins or carbohydrates that train the immune system to zero in on a particular microbe and wipe it out. The Pfizer and Moderna vaccines instead contain genetic recipes for manufacturing the spike protein that SARS-CoV-2, the virus that causes COVID-19, uses to latch on to cells it infects.

In December 2020, Stanford Medicine began inoculating people with the Pfizer vaccine. This spurred Pulendran’s desire to assemble a complete report card on the immune response to it. 

Bali Pulendran
Bali Pulendran © Med Stanford

The team selected 56 healthy volunteers and drew blood samples from them at multiple time points preceding and following the first and second shots. The researchers found that the first shot increases SARS-CoV-2-specific antibody levels, as expected, but not nearly as much as the second shot does. The second shot also does things the first shot doesn’t do, or barely does. 

“The second shot has powerful beneficial effects that far exceed those of the first shot,” Pulendran said. “It stimulated a manifold increase in antibody levels, a terrific T-cell response that was absent after the first shot alone, and a strikingly enhanced innate immune response.”

Unexpectedly, Pulendran said, the vaccine — particularly the second dose — caused the massive mobilization of a newly discovered group of first-responder cells that are normally scarce and quiescent.

First identified in a recent vaccine study led by Pulendran, these cells — a small subset of generally abundant cells called monocytes that express high levels of antiviral genes — barely budge in response to an actual COVID-19 infection. But the Pfizer vaccine induced them. 

This special group of monocytes, which are part of the innate museum, constituted only 0.01% of all circulating blood cells prior to vaccination. But after the second Pfizer-vaccine shot, their numbers expanded 100-fold to account for a full 1% of all blood cells. In addition, their disposition became less inflammatory but more intensely antiviral. They seem uniquely capable of providing broad protection against diverse viral infections, Pulendran said. 

“The extraordinary increase in the frequency of these cells, just a day following booster immunization, is surprising,” Pulendran said. “It’s possible that these cells may be able to mount a holding action against not only SARS-CoV-2 but against other viruses as well.”

Pulendran is a member of the Institute for Immunity Transplantation & Infection and Stanford Bio-X and a faculty fellow of Stanford ChEM-H.

Other Stanford study co-authors are basic life science research scientist Chunfeng Li, PhD; research scientists Natalia Sigal, PhD, Sangeeta Kowli, PhD, and Sheena Gupta, PhD; postdoctoral scholars Yupeng Feng, PhD, Florian Wimmers, PhD, Vamsee Mallajosyula, PhD, and Fei Gao, PhD; graduate student Lilit Grigoryan; life science research professionals Sofia Maysel-Auslender, Meera Trisal and Allan Feng; former life science research professional Shaurya Dhingra; undergraduate student Sarah Chang; clinical research assistant Mihir Shah; clinical and laboratory research assistant Allie Lee; Sharon Chinthrajah, MD, associate professor of medicine; Sayantani Sindher, MD, clinical associate professor of medicine; Holden Maecker, PhD, professor of microbiology and immunology and director of Stanford’s Human Immune Monitoring Center; Scott Boyd, PhD, associate professor of pathology; Mark Davis, PhD, professor of microbiology and director of Stanford’s Institute for Immunity, Transplantation and Infection; and PJ Utz, MD, professor of medicine.

Researchers at Billerica, Massachusetts-based Quanterix and Emory University also contributed to the study.

The work was funded by the National Institutes of Health (grants U19AI090023, U19AI057266, U24AI120134, P51OD011132, S10OD026799, R01AI123197-04, U01AI150741-01S1 and AI057229), Open Philanthropy, the Sean Parker Cancer Institute, the Soffer Endowment, the Violetta Horton Endowment, Stanford University, the Henry Gustav Floren Trust, the Parker Foundation, the Cooperative Centers on Human Immunology and the Crown Foundation.

Stanford’s Institute for Immunity, Transplantation and Infection also supported the work.

Featured image: Stanford undergraduate student Houston Heimuli is inoculated with a COVID-19 vaccine. © Steve Fisch


Provided by Stanford Medicine

Protein-based Vaccine Candidate Combined With Potent Adjuvant Yields Effective SARS-CoV-2 Protection (Medicine)

A new protein-based vaccine candidate combined with a potent adjuvant provided effective protection against SARS-CoV-2 when tested in animals, suggesting that the combination could add one more promising COVID-19 vaccine to the list of candidates for human use.

The protein antigen, based on the receptor binding domain (RBD) of SARS-CoV-2, was expressed in yeast instead of mammalian cells – which the authors say could enable a scalable, temperature-stable, low-cost production process well suited for deployment in the developing world.

In a study by Maria Pino and colleagues, the adjuvant – a TLR7/TLR8 agonist named 3M-052, formulated with alum – substantially improved performance of the vaccine compared with vaccine adjuvanted with alum alone, inducing stronger antibody and T cell responses in vaccinated rhesus macaques.

The vaccine and adjuvant combination also significantly reduced the quantity of virus in the respiratory tracts of macaques challenged by infection with SARS-CoV-2, and reduced lung inflammation as well.

Pino et al. vaccinated 5 macaques with the RBD protein and the 3M-052/alum adjuvant and another 5 with the RBD protein and alum alone, each at 0, 4, and 9 weeks; they also included 5 unvaccinated macaques as controls. The vaccine and adjuvant combination induced more neutralizing antibodies with higher binding affinity for the virus RBD and also enhanced CD4+ and CD8+ T cell responses compared with the alum-only formulation.

About one month after the third round of vaccinations, the researchers then infected the macaques with SARS-CoV-2, and noted the macaques vaccinated with the novel adjuvant formulation showed a reduced viral load in their nasal mucus and lung fluid, as well as fewer inflammatory cytokines in their plasma.

Featured image: The RBD+3M-052-alum vaccine induces robust humoral immunity in RMs. © Authors


Reference: Maria Pino, Talha Abid, Susan Pereira Ribeiro, Venkata Viswanadh Edara, Katharine Floyd, Justin C. Smith, Muhammad Bilal Latif, Gabriela Pacheco-Sanchez, Debashis Dutta, Shelly Wang, Sanjeev Gumber, Shannon Kirejczyk, Joyce Cohen, Rachelle L. Stammen, Sherrie M. Jean, Jennifer S. Wood, Fawn Connor-Stroud, Jeroen Pollet, Wen-Hsiang Chen, Junfei Wei, Bin Zhan, Jungsoon Lee, Zhuyun Liu, Ulrich Strych, Neeta Shenvi, Kirk Easley, Daniela Weiskopf, Alessandro Sette, Justin Pollara, Dieter Mielke, Hongmei Gao, Nathan Eisel, Celia C. LaBranche, Xiaoying Shen, Guido Ferrari, Georgia D. Tomaras, David C. Montefiori, Rafick P. Sekaly, Thomas H. Vanderford, Mark A. Tomai, Christopher B. Fox, Mehul S. Suthar, Pamela A. Kozlowski, Peter J. Hotez, Mirko Paiardini, Maria Elena Bottazzi, Sudhir Pai Kasturi, “A yeast expressed RBD-based SARS-CoV-2 vaccine formulated with 3M-052-alum adjuvant promotes protective efficacy in non-human primates”, Science Immunology  15 Jul 2021: Vol. 6, Issue 61, eabh3634 DOI: https://doi.org/10.1126/sciimmunol.abh3634


Provided by AAAS

COVID-19 Vaccine Generates Immune Structures Critical for Lasting Immunity (Medicine)

Vaccines likely induce strong, persistent immunity to COVID-19

The first two COVID-19 vaccines authorized for emergency use by the Food and Drug Administration (FDA) employed a technology that had never before been used in FDA-approved vaccines. Both vaccines performed well in clinical trials, and both have been widely credited with reducing disease, but concerns remain over how long immunity induced by the new vaccine technology will last.

Now, a study from researchers at Washington University School of Medicine in St. Louis, published June 28 in the journal Nature, has found evidence that the immune response to such vaccines is both strong and potentially long-lasting. Nearly four months after the first dose, people who received the Pfizer vaccine still had so-called germinal centers in their lymph nodes churning out immune cells directed against SARS-CoV-2, the virus that causes COVID-19. Germinal centers, which form as the result of natural infection or vaccination, are boot camps for immune cells, a place where inexperienced cells are trained to better recognize the enemy and weapons are sharpened. A better germinal center response may equal a better vaccine.

Moreover, vaccination led to high levels of neutralizing antibodies effective against three variants of the virus, including the Beta variant from South Africa that has shown some resistance to vaccines. Vaccination induced stronger antibody responses in people who had recovered from SARS-CoV-2 infection compared to those who had never been infected.

In April, both Pfizer and Moderna reported that their vaccines provided at least six months of protection. Their reports were based on tracking whether vaccinated people came down with COVID-19. Other groups have monitored antibody levels in the blood and concluded that the vaccine provides at least months of protection. But nobody had looked to see how the immune response was developing in the body, which could provide important clues to the strength and persistence of the immune response without requiring years of follow-up.

“Germinal centers are the key to a persistent, protective immune response,” said senior author Ali Ellebedy, PhD, an associate professor of pathology & immunology, of medicine and of molecular microbiology. “Germinal centers are where our immune memories are formed. And the longer we have a germinal center, the stronger and more durable our immunity will be because there’s a fierce selection process happening there, and only the best immune cells survive. We found that germinal centers were still going strong 15 weeks after the vaccine’s first dose. We’re still monitoring the germinal centers, and they’re not declining; in some people, they’re still ongoing. This is truly remarkable.”

Scientists don’t fully understand why some vaccines, such as the one for smallpox, induce strong protection that lasts a lifetime, while others, such as the vaccine for whooping cough, require regular boosters. But many suspect that the difference lies in the quality of the germinal centers induced by different vaccines.

The Pfizer and Moderna vaccines were created with mRNA technology. Unlike most vaccines, which provide bits of viral or bacterial proteins to trigger an immune response, mRNA-based vaccines provide instructions for the body to build and release foreign proteins, such as the spike protein in the case of the SARS-CoV-2 virus. To assess whether this new kind of vaccine induces a good germinal center response, Ellebedy and co-first author Jackson Turner, PhD, an instructor in pathology & immunology, teamed up with co-senior author Rachel Presti, MD, PhD, an associate professor of medicine, and co-first author Jane O’Halloran, MD, PhD, an assistant professor of medicine, and started the study once the first COVID-19 vaccine became available in mid-December 2020.

The team enlisted the help of co-authors Sharlene Teefey, MD, and William Middleton, MD, both professors of radiology, to perform ultrasound-guided sampling of the minuscule germinal centers in lymph nodes in the armpit. Teefey and Middleton extracted cells from 14 people who received the Pfizer vaccine. Samples were obtained three weeks after the first dose (just prior to administration of the second dose), and at weeks four, five and seven. Ten of the participants gave additional samples 15 weeks after the first dose. None of the participants previously had been infected with the virus that causes COVID-19.

Three weeks after the first dose, all 14 participants had formed germinal centers with B cells producing antibodies that target a key SARS-CoV-2 protein. The response expanded greatly after the booster shot and then stayed high. Even 15 weeks after the first dose, eight of 10 people still had detectable germinal centers containing B cells targeting the virus.

“This is evidence of a really robust immune response,” Presti said. “Your immune system uses germinal centers to perfect the antibodies so they can bind well and last as long as possible. The antibodies in the blood are the end result of the process, but the germinal center is where it is happening.”

The researchers also obtained blood samples from 41 people who received the Pfizer vaccine, including eight who previously had been infected with the virus that causes COVID-19. Samples were obtained prior to the administration of each dose of the vaccine, as well as at weeks four, five, seven and 15 after the first dose. In people without prior exposure to the virus, antibody levels rose slowly after the first dose and peaked one week after the second. People who previously had been infected already had antibodies in their blood before the first dose. Their levels shot up quickly after the first dose and peaked higher than the uninfected participants’ levels.

“We didn’t set out to compare the effectiveness of vaccination in people with and without a history of infection, but when we looked at the data we could see an effect,” O’Halloran said. “If you’ve already been infected and then you get vaccinated, you get a boost to your antibody levels. The vaccine clearly adds benefit, even in the context of prior infection, which is why we recommend that people who have had COVID-19 get the vaccine.”

This study was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH), grant and contract numbers U01AI141990, 1U01AI150747, R01 AI157155, AI134907, 5T32CA009547, HHSN272201400006C, HHSN272201400008C and 75N93019C00051; the NIH, grant number UL1TR001439; the Sealy & Smith Foundation; the Kleberg Foundation; the John S. Dunn Foundation; the Amon G. Carter Foundation; the Gilson Longenbaugh Foundation; the Summerfield Robert Foundation; and a Helen Hay Whitney Foundation postdoctoral fellowship. This study utilized samples obtained from the Washington University School of Medicine’s COVID-19 biorepository supported by the NIH/National Center for Advancing Translational Sciences, grant number UL1 TR002345.

Featured image: Ali Ellebedy, PhD, (right) an associate professor of pathology & immunology at Washington University School of Medicine in St. Louis, discusses data with Jackson Turner, PhD, a postdoctoral researcher. Ellebedy, Turner and colleagues have found that the COVID-19 vaccine triggers the development of an immune structure critical to strong and lasting immunity. © Matt Miller


Reference: 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 P-Y, Krammer F, Teefey SA, Diamond MS, Presti RM, Ellebedy AH. SARS-CoV-2 mRNA vaccines induce persistent germinal centre responses in humans. Nature. June 28, 2021. Link to paper


Provided by WUSTL

Scientists Discover How Dengue Vaccine Fails to Protect Against Disease (Medicine)

UNC School of Medicine scientists led by Aravinda de Silva, PhD, identified the small subpopulation of antibodies in vaccinated children that correlate with protection against dengue fever. This research should help shape better vaccines for one of the most widespread infectious diseases in the world.

Developing a viable vaccine against dengue virus has proved difficult because the pathogen is actually four different virus types, or serotypes. Unless a vaccine protects against all four, a vaccine can wind up doing more harm than good.

To help vaccine developers overcome this hurdle, the UNC School of Medicine lab of Aravinda de Silva, PhD, professor in the UNC Department of Microbiology and Immunology, investigated samples from children enrolled in a dengue vaccine trial to identify the specific kinds of antibody responses that correlate with protection against dengue virus disease. In doing so, the researchers discovered that a small subpopulation of antibodies binding to unique sites on each serotype are linked to protection. The research, published in the Journal of Clinical Investigation, provides important information for vaccine developers to consider when creating a dengue vaccine, which has long eluded scientists.

Cameron Adams © UNC Health

The four dengue virus serotypes are mosquito-borne flaviviruses that infect hundreds of millions of individuals each year in Southeast Asia, western Pacific Islands, Africa, and Latin America. Nearly 100 million individuals report flu-like symptoms. Though rarely deadly, the virus can cause severe illness, especially when a person who was previously infected with one serotype (and recovers) is then infected by a second serotype. This happens because antibodies from the first infection help the virus replicate during the second infection through a process called antibody dependent enhancement. A dengue vaccine induced antibody response weighted towards a single dengue virus serotype can mimic this phenomenon.

Several vaccines have been in clinical development for years, and most show that they induce neutralizing antibodies against all four serotypes. Yet, research has also shown that the creation of neutralizing antibodies alone does not correlate to protection against clinical disease. The de Silva lab conducted experiments to compare the properties of antibodies against wild-type Dengue viruses and the properties of antibodies produced by a leading vaccine candidate – Dengvaxia – which the pharmaceutical company Sanofi Pasteur created using all four dengue virus serotypes in one formulation.

Experiments led by Sandra Henein, research associate in the UNC Department of Microbiology and

Sandra Henein © UNC Health

Immunology, and Cameron Adams, a medical and graduate student in the UNC Medical Scientist Training Program (MD/PhD), showed that wild type infections induced neutralizing and protective antibodies that recognized a part of the virus – an epitope – unique to each serotype. The vaccine, though, mainly stimulated neutralizing antibodies that recognized epitopes common among all serotypes. In vaccine trials, these antibodies did not protect children from dengue.   In the past, researchers have considered all dengue neutralizing antibodies to be protective in people. This appears to not be the case, according to this UNC-led research.

“Our results suggest that a safe and effective dengue virus vaccine needs to stimulate neutralizing antibodies targeting unique sites on each of the four dengue serotypes ,” Adams said. “Not merely the neutralizing antibodies against cross-reactive epitopes common to all four dengue types.”

Henein and Adams are co-first authors of the JCI paper, and de Silva is senior author. Other authors are Matthew Bonaparte, Janice Moser, Alina Munteanu, all from Sanofi Pasteur, and Ralph Baric, from UNC-Chapel Hill.

The National Institute of Allergy and Infectious Diseases funded this work through R01 grants AI107731 and AI125198.


Reference: Sandra Henein, … , Ralph Baric, Aravinda M. Desilva, “Dengue vaccine breakthrough infections reveal properties of neutralizing antibodies linked to protection”, J Clin Invest. 2021. https://doi.org/10.1172/JCI147066.


Provided by UNC Health

Creating A Needle-free COVID-19 Vaccine (Medicine)

Vaccines are mostly synonymous with needles, an efficient and effective way to provide immunity to myriad infections. As COVID-19 vaccination efforts roll out across the U.S. and the world, some experts believe that a vaccine administered through the nose could be just as effective and easier to administer. A cover story in Chemical & Engineering News, the weekly newsmagazine of the American Chemical Society, explains the pros and cons of nasal vaccines.

SARS-CoV-2, the virus that causes COVID-19, often enters the body through the nose when a person inhales. From there it encounters a network of mucosal membranes that form the body’s first line of immune defense, writes Associate Editor Ryan Cross. The cells of mucus membranes create a special type of antibody, which experts say can provide both mucosal and systemic immunity when triggered by a vaccine that is sprayed into the nasal cavity. In contrast, injectable vaccines only trigger a systemic immune response. The COVID-19 vaccines currently available in the U.S. and Europe are highly effective, but there is not enough supply to inoculate the entire world. So, an intranasal version could help offset the disparity, on top of being easier to use.

However, the mucosal immune system is difficult to study, and intranasal vaccines have not generated much interest in recent years. Only one intranasal vaccine (AstraZeneca’s FluMist) has come to market in the U.S., but its higher cost and mixed results compared to the typical flu shot have made it unpopular. In addition, the way the vaccine is administered means that a patient could sneeze out part of it before it’s absorbed by the body, making it unclear how much of the dose a person gets. Despite these challenges, scientists and biotech companies are still working to make intranasal vaccines for respiratory illnesses. The pandemic has provided an opportunity to run clinical trials, and at least one company hopes to manufacture and distribute nasal doses of the COVID-19 vaccine by the end of the year. 

The study, ““Intranasal vaccines aim to stop COVID-19 where it starts”, Chemical & Engineering News

Featured image credit: C&EN/Shutterstock


Provided by American Chemical Society

Covid Vaccine Linked To Low Platelet Count (Medicine)

A condition that affects the blood, known as idiopathic thrombocytopenic purpura (ITP), may be associated the Oxford-AstraZeneca vaccine in rare cases, a nationwide study suggests.

The very small increased risk of the condition – which is characterised by low platelet counts – is estimated to be 11 per million doses, similar to figures seen in vaccines for flu and MMR.

A low number of platelets – blood cells that help prevent blood loss when vessels are damaged – can result in no symptoms or can lead to an increased risk of bleeding or, in some cases, clotting.

Researchers say that the increased chance of developing ITP after receiving the vaccine remains smaller than the risk of developing it because of Covid-19 and should not deter the roll out of the vaccine programme.

The same risk was not found for the Pfizer-BioNTech vaccine. Other vaccines were not included in the study.

Comparative risk

Experts recommend that recipients of the Oxford-AstraZeneca vaccine should be made aware of the slight increased risks of ITP, but also stress that the risk of developing these disorders from Covid-19 is potentially much higher.

The Medical and Healthcare products Regulatory Agency (MHRA) had previous reported low platelet counts in combination with blood clots following vaccination with the Oxford-AstraZeneca vaccine, estimated to occur at a rate of approximately 13 per million first doses.

Experts say the new study’s specific findings about ITP are likely to be a manifestation of this general condition. The MHRA is actively monitoring the situation.

The study of 5.4 million people in Scotland, of whom 2.5m had received their first vaccine dose, is the first analysis of ITP, clotting and bleeding events following vaccination for an entire country.

Clotting

Researchers were unable to establish a definitive link between other forms of clotting – including the rare form called cerebral venous sinus thrombosis or CVST – due to the very low number of cases in vaccinated people included in the study.

Those at most risk from ITP tended to be older – a median age of 69 years old – and had at least one underlying chronic health problem such as coronary heart disease, diabetes or chronic kidney disease.

Data analysis

The research team, led by the University of Edinburgh, analysed a dataset as part of the EAVE II project, which uses anonymised linked patient data to track the pandemic and the vaccine roll out in real time.

They investigated data up to 14 April 2021 for people in Scotland who had received the first dose of either vaccine. By this date more than 1.7 million had an Oxford-AstraZeneca jab and some 800,000 had a dose of the Pfizer-BioNTech vaccine.

Researchers – working in collaboration with the Universities of Strathclyde, Aberdeen, Glasgow, Oxford, Swansea and St Andrew’s, Victoria University of Wellington, Queen’s University, Belfast, and Public Health Scotland (PHS) – also looked at health records dating back to September 2019 to investigate any previous issues with ITP, clotting or bleeding disorders.

The data – including GP records on vaccination, hospital admissions, death registrations and laboratory test results – were then compared with those who were yet to be vaccinated to determine if any clotting events were outside what would have been expected pre-pandemic.

The data indicated that there was a slight increase in ITP in the second week following vaccination for those who received the Oxford-AstraZeneca vaccine and possibly also increased risk of arterial clotting and bleeding events.

“This careful analysis of an entire country’s vaccination programme, which involved the study of over 2.5m first dose vaccines, has found a small increase in the risk of ITP, clotting and bleeding events following the Oxford-AstraZeneca vaccine. This very small risk is important, but needs to be seen within the context of the very clear benefits of the vaccines and potentially higher risks of these outcomes in those who develop Covid-19.”, said Professor Aziz Sheikh, Director of the University of Edinburgh’s Usher Institute and EAVE II study lead

Other vaccines

The 11 cases of ITP per million vaccine doses is similar to numbers seen for Hepatitis B, MMR and flu vaccines, which range from 10 to 30 cases of ITP per million doses.

The team found no adverse events in relation to ITP, clotting or bleeding in their analysis for the Pfizer-BioNTech vaccine.

Experts say that while the study adds to the evidence linking the Oxford-AstraZeneca vaccination to blood clots and ITP, a causal association has not yet been definitively demonstrated. This is under active investigation.

Researchers say a two-week lag for hospital data may mean some data are missing, which possibly limits the study’s findings.

The study also included relatively few young vaccinated people under 40, especially for the Oxford-AstraZeneca vaccine because the Scottish vaccination programme followed the recommendations of the Joint Committee on Vaccination and Immunisation, which prioritised vaccinations for older and vulnerable adults.

Support

The results are published in the journal Nature Medicine. The study was funded by the Medical Research Council, UK Research and Innovation Industrial Strategy Challenge Fund and Health Data Research UK (HDR UK), and was supported by the Scottish Government.

Additional support was provided through the Scottish Government Director-General Health and Social Care, and the UKRI COVID-19 National Core Studies Data and Connectivity programme led by HDR UK.

If a member of the public experiences side effects following vaccination with Oxford AstraZeneca vaccine, or wishes to find out more, the researchers advise that they seek information contained in the AstraZeneca COVID-19 vaccine and rare blood clots leaflet which can be accessed on the NHS Inform web page.

“Reassuringly, we did not identify any overall increased risk of ITP, clotting and bleeding events in those receiving the Pfizer-BioNTech mRNA vaccine. We are now planning to update our analysis as the vaccine programme is being extended to younger, healthier individuals and as new vaccines are becoming available.”, said Professor Colin Simpson, Victoria University of Wellington.

“This study shows the advantage of being able to link together large national data sets to provide near real time information of vaccine safety, using a number of analytical methods.  An important next step is to replicate this work in other settings to ensure that the findings are robust.”, said Professor Chris Robertson, University of Strathclyde and Public Health Scotland.

Reference

Simpson, C.R., Shi, T., Vasileiou, E. et al. First-dose ChAdOx1 and BNT162b2 COVID-19 vaccines and thrombocytopenic, thromboembolic and hemorrhagic events in Scotland. Nat Med (2021). https://doi.org/10.1038/s41591-021-01408-4


Provided by University of Edinburgh