Staff organize COVID-19 test packets at the Sanderford Road Park COVID-19 testing site on Tuesday, January 19, 2021 in Raleigh, NC.

Is it better to get immunity from COVID or vaccines?

  • June 17, 2021

Staff organize COVID-19 test packets at the Sanderford Road Park COVID-19 testing site on Tuesday, January 19, 2021 in Raleigh, NC.

Staff organize COVID-19 test packets at the Sanderford Road Park COVID-19 testing site on Tuesday, January 19, 2021 in Raleigh, NC.

rwillett@newsobserver.com

Research shows both coronavirus infection and vaccination offers immunity that can protect people from getting sick again. But by how much and for how long remains unclear — a scientific gap that only time could fill.

Regardless of how immunity is acquired, there’s no telling whose bodies will or won’t create effective antibodies, and why they last longer for some than others; doctors speculate age or certain medical conditions might play a role.

It also doesn’t help that the testing shortage that plagued the nation at the beginning of the pandemic will forever shield researchers from understanding the true impact of COVID-19.

The Centers for Disease Control and Prevention estimates that between February 2020 and March 2021, there were about 114.6 million total coronavirus infections in the U.S.. That’s about 81.1 million more cases than are confirmed as of June 17.

While people can gain immunity from both infection and vaccination, antibodies created from both routes target different parts of the virus, which leads to variations in the quality of protection.

It’s like a coin flip: risk contracting COVID-19 — and potentially becoming a long-hauler — or getting vaccinated. Some argue the final outcome is similar, but one is far more dangerous than the other.

Here’s what the latest data show about immunity from prior infection and vaccines.

Natural immunity from coronavirus infection

There are certain illnesses in which infection can offer more protection than a vaccine.

For example, coming down with measles or mumps is said to confer lifelong immunity to the virus, but some people who get the vaccine may still get infected, although the shots still limit and prevent the spread of outbreaks.

But if the novel coronavirus is anything like others in the coronavirus family, like the Middle East Respiratory Syndrome (MERS), then permanent protection after infection is unlikely.

Studies offer some positive clues, however.

Research published in February found that coronavirus patients gained “substantial immune memory” that involved all four major parts of the immune system: memory B cells, antibodies, memory CD4+ T cells and memory CD8+ T cells.

This protection lasted about six months after infection in most people, but for some, it remained for up to eight months, suggesting it could last even longer in some cases.

Separate research posted in April showed a history of COVID-19 among U.K. patients was associated with an 84% lower risk of reinfection for about seven months after testing positive.

Another non-peer reviewed study published in June found that over five months, 1,359 American health care workers who previously had COVID-19 and didn’t get vaccinated stayed clear of reinfection. The Cleveland Clinic researchers said, in the context of a short supply of vaccines globally, “a practical and useful message would be to consider symptomatic COVID-19 to be as good as having received a vaccine,” adding that people who’ve had the coronavirus “are unlikely to benefit from COVID-19 vaccination.”

While scientists cannot predict who will develop natural immunity, evidence shows people who had severe COVID-19 are more likely to develop a stronger immune response than those who had milder forms of the disease.

Immunity from COVID-19 vaccines

It’s also true that research shows COVID-19 vaccines offer protection against reinfection, although “breakthrough cases” can occur because no vaccine is 100% effective.

However, studies have found vaccine-derived antibodies are more robust compared to those from natural infection — and the job is done without causing illness or other long-term complications often brought on by the disease.

Two doctors from Italy compared the process of infection and vaccination in relation to variants to the plot of an action movie.

It “begins with a character (the virus) running freely across the globe, eluding capture until being finally sent to jail (built by natural immunity). However, if this prison is not secure enough, the virus could escape, aided by certain mutations,” Dr. Emanuele Andreano and Dr. Rino Rappuoli of the Monoclonal Antibody Discovery Lab, wrote in Nature. “Vaccine-induced immunity… should help ensure those escape routes are securely closed.”

An April study that has not been peer-reviewed found that two doses of either the Pfizer or Moderna vaccines offered 10 times higher levels of antibodies compared to those developed after natural infection.

Another April paper showed that people who were previously infected with the coronavirus experienced significant boosts in their preexisting antibodies after two doses of the Pfizer vaccine, which also offered protection against coronavirus variants.

“Vaccines actually, at least with regard to SARS-CoV-2, can do better than nature… They are better than the traditional response you get from natural infection,” White House chief medical adviser Dr. Anthony Fauci said during a COVID-19 briefing in May.

Exactly why vaccines appear to generate more robust immunity than natural infection remains unclear, but Dr. Sabra Klein, a virologist and professor of immunology at Johns Hopkins Bloomberg School of Public Health, said infection and vaccination work in different ways.

“The immune system of people who have been infected has been trained to target all these different parts of the virus called antigens. You’d think that would provide the strongest immunity, but it doesn’t,” Klein said. “The Pfizer or Moderna vaccines target just the spike protein — the part of the virus that is essential for invading cells.

“It’s like a big red button sitting on the surface of the virus. It’s really sticking out there, and it’s what our immune system sees most easily,” she continued. “By focusing on this one big antigen, it’s like you’re making our immune system put blinders on and only be able to see that one piece of the virus.”

In other words, vaccines work to strengthen immune responses gained during natural infection; that’s why health experts advise people who’ve had COVID-19 to still get vaccinated.

“There’s nothing deleterious about getting a boost to an immune response that you’ve had before,” Dr. Marion Pepper, an immunologist at the University of Washington in Seattle, told The New York Times. “You could get an actually even better immune response by boosting whatever immunity you had from the first infection by a vaccine.”

Follow more of our reporting on Full coverage of coronavirus in Washington


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Katie Camero is a McClatchy National Real-Time Science reporter based in Miami. She’s an alumna of Boston University and has reported for the Wall Street Journal, Science, and The Boston Globe.

'Mosquito smoothie' innovation boosts future malaria vaccine potential

‘Mosquito smoothie’ innovation boosts future malaria vaccine potential

  • June 17, 2021

A faster method for collecting pure malaria parasites from infected mosquitos could accelerate the development of new, more potent malaria vaccines.

The new method, developed by a team of researchers led by Imperial College London, enables more parasites to be isolated rapidly with fewer contaminants, which could simultaneously increase both the scalability and efficacy of malaria vaccines.

The parasite that causes malaria is becoming increasingly resistant to antimalarial drugs, with the mosquitoes that transmit the disease also increasingly resistant to pesticides. This has created an urgent need for new ways to fight malaria, which is the world’s third-most deadly disease in under-fives, with a child dying from malaria every two minutes.

Existing malaria vaccines that use whole parasites provide moderate protection against the disease. In these vaccines, the parasites are ‘attenuated’ – just like some flu vaccines and the MMR vaccine – so they infect people and raise a strong immune response that protects against malaria, but don’t cause disease themselves.

However, these vaccines require several doses, with each dose requiring potentially tens of thousands of parasites at an early stage of their development, known as sporozoites. Sporozoites are normally found in the salivary glands of mosquitoes, and in a natural infection are passed to humans when the mosquito bites. They then travel to the human liver, where they prepare to cause infection in the body.

Extracting sporozoites for use in a live vaccine currently requires manual dissection of the mosquito salivary glands – miniscule structures behind the mosquito head – by a skilled technician, which is a time-consuming and costly process.

The new method, described today in Life Science Alliance, vastly speeds up this process by effectively creating a ‘mosquito smoothie’ and then filtering the resulting liquid by size, density and electrical charge, leaving a pure sporozoite product suitable for vaccination. Importantly, no dissection is required.

Lead researcher Professor Jake Baum, from the Department of Life Sciences at Imperial, said: “Creating whole-parasites vaccines in large enough volumes and in a timely and cost-effective way has been a major roadblock for advancing malaria vaccinology, unless you can employ an army of skilled mosquito dissectors. Our new method presents a way to radically cheapen, speed up and improve vaccine production.”

But it’s not just about speed and cost. Traditional dissection methods struggle to remove all contaminants, such as proteins from the salivary glands, which are often extracted with sporozoites. The extra debris is likely to affect the infectivity of the sporozoites once they are inside the body, and could even affect how the immune system responds, impacting the efficacy of any whole parasite vaccine.

The new method also tackles this problem, resulting in pure uncontaminated sporozoite samples. The team discovered that, as well as being purer, sporozoites produced were surprisingly more infectious, hinting that vaccines produced using their method may require a much lower dose of sporozoites.

First author of the study Dr Joshua Blight, from the Department of Life Sciences at Imperial, said: “With this new approach we not only improve the scalability of vaccine production, but our isolated sporozoites may actually prove to be more potent as a vaccine, giving us additional bang per mosquito buck.”

The team developed and tested their method with both human and rodent malaria parasites. They then tested the rodent version as a vaccine in mice, and found that when exposed to an infected mosquito bite, vaccinated mice showed 60-70 per cent protection when immunisations were given into muscle. When the same sporozoites were given directly into the blood stream (intravenously) protection was 100 per cent, known as ‘sterile’ protection.

The researchers are now developing the method further in readiness for mass manufacture of sporozoites under good manufacturing practice (GMP) conditions in order to produce a vaccine ready for human challenge trials. The plan is that participants would be given vaccine-grade sporozoites produced using this method and then purposefully bitten by an infected mosquito.

Looking beyond vaccines the researchers also say their method should help accelerate studies of sporozoite biology in general, which could in turn lead to fresh insights into the liver stage of malaria and new drug and vaccine regimes.

###

The research was funded by the Wellcome Trust and the Bill & Melinda Gates Foundation.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

Next-Generation COVID-19 Vaccines Could Stimulate Another Arm of the Immune System

Next-Generation COVID-19 Vaccines Could Stimulate Another Arm of the Immune System

  • June 17, 2021

A new study looking at the way human cells activate the immune system in response to SARS-CoV-2 infection could open the door to even more effective and powerful vaccines against the coronavirus and its rapidly emerging variants keeping the global pandemic smoldering.

Researchers from Boston University’s National Emerging Infectious Diseases Laboratories (NEIDL) and the Broad Institute of MIT and Harvard say it’s the first real look at exactly what types of “red flags” the human body uses to enlist the help of T cells—killers sent out by the immune system to destroy infected cells. Until now, COVID vaccines have been focused on activating a different type of immune cell, B cells, which are responsible for creating antibodies. Developing vaccines to activate the other arm of the immune system—the T cells—could dramatically increase immunity against coronavirus, and importantly, its variants.

In their findings, published in Cell, the researchers say current vaccines might lack some important bits of viral material capable of triggering a holistic immune response in the human body. Based on the new information, “companies should reevaluate their vaccine designs,” says Mohsan Saeed, a NEIDL virologist and the co-corresponding author of the paper.

Saeed, a BU School of Medicine assistant professor of biochemistry, performed experiments on human cells infected with coronavirus. He isolated and identified those missing pieces of SARS-CoV-2 proteins inside one of the NEIDL’s Biosafety Level 3 (BSL-3) labs. “This was a big undertaking because many research techniques are difficult to adapt for high containment levels [such as BSL-3],” Saeed says. “The overall coronavirus research pipeline we’ve created at the NEIDL, and the support of our entire NEIDL team, has helped us along the way.”

Saeed got involved after he was contacted by genetic sequencing experts at the Broad Institute, computational geneticists Pardis Sabeti and Shira Weingarten-Gabbay. They hoped to identify fragments of SARS-CoV-2 that activate the immune system’s T cells.

“The emergence of viral variants, an active area of research in my lab, is a major concern for vaccine development,” says Sabeti, a leader in the Broad Institute’s Infectious Disease and Microbiome Program. She is also a Harvard University professor of systems biology, organismic and evolutionary biology, and immunology and infectious disease, as well as a Howard Hughes Medical Institute investigator.

“We swung into full action right away because my laboratory had [already] generated human cell lines that could be readily infected with SARS-CoV-2,” Saeed says. The group’s efforts were spearheaded by two members of the Saeed lab: Da-Yuan Chen, a postdoctoral associate, and Hasahn Conway, a lab technician.

From the outset of COVID pandemic in early 2020, scientists around the world knew the identity of 29 proteins produced by SARS-CoV-2 virus in infected cells—viral fragments that now make up the spike protein in some coronavirus vaccines, such as the Moderna, Pfizer-BioNTech, and Johnson & Johnson vaccines. Later, scientists discovered another 23 proteins hidden inside the virus’ genetic sequence; however, the function of these additional proteins was a mystery until now. The new findings of Saeed and his collaborators reveal—unexpectedly and critically—that 25 percent of the viral protein fragments that trigger the human immune system to attack a virus come from these hidden viral proteins.

How exactly does the immune system detect these fragments? Human cells contain molecular “scissors”—called proteases—that, when the cells are invaded, hack off bits of viral proteins produced during infection. Those bits, containing internal proteins exposed by the chopping-up process—like the way the core of an apple is exposed when the fruit is segmented—are then transported to the cell membrane and pushed through special doorways. There, they stick outside the cell acting almost like a hitchhiker, waving down the help of passing T cells. Once T cells notice these viral flags poking through infected cells, they launch an attack and try to eliminate those cells from the body. And this T cell response isn’t insignificant—Saeed says there are links between the strength of this response and whether or not people infected with coronavirus go on to develop serious disease.

“It’s quite remarkable that such a strong immune signature of the virus is coming from regions [of the virus’ genetic sequence] that we were blind to,” says Weingarten-Gabby, the paper’s lead author and postdoctoral fellow in the Sabeti lab. “This is a striking reminder that curiosity-driven research stands at the basis of discoveries that can transform the development of vaccines and therapies.”

“Our discovery … can assist in the development of new vaccines that will mimic more accurately the response of our immune system to the virus,” Sabeti says.

T cells not only destroy infected cells but also memorize the virus’ flags so that they can launch an attack, stronger and faster, the next time the same or a different variant of the virus appears. That’s a crucial advantage, because Saeed and his collaborators say the coronavirus appears to delay the cell’s ability to call in immune help.

“This virus wants to go undetected by the immune system for as long as possible,” Saeed says. “Once it’s noticed by the immune system, it’s going to be eliminated, and it doesn’t want that.”

Based on their findings, Saeed says, a new vaccine recipe, incorporating some of the newly discovered internal proteins making up the SARS-CoV-2 virus, would be effective in stimulating an immune response capable of tackling a wide swath of newly emerging coronavirus variants. And given the speed with which these variants continue to appear around the world, a vaccine that can provide protection against all of them would be a game changer. 

Reference:
 Weingarten-Gabbay S, Klaeger S, Sarkizova S, et al. Profiling SARS-CoV-2 HLA-I peptidome reveals T cell epitopes from out-of-frame ORFs. Cell. doi: 10.1016/j.cell.2021.05.046.

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

The complex situation for immunocompromised people and COVID-19 vaccines

The complex situation for immunocompromised people and COVID-19 vaccines

  • June 16, 2021

When Margaret Collins, a 43-year-old geologist from Fort Worth, Texas, got her first dose of the Moderna vaccine January 6, she came home and cried.

“I was finally getting the shot,” she says. “I saw it as a step back to the life that I loved.”

A self-described extrovert, Collins became a hermit during the pandemic. She and her husband rarely stepped outside, and never without a mask. Her caution is warranted because she suffers from a generalized autoimmune disorder that includes hepatitis, psoriatic arthritis, vitiligo, and type 1 diabetes. Collins is also particularly vulnerable to COVID-19 because she received a donated pancreas and kidney in 2014 and takes three medications to suppress her immune system so her body doesn’t reject those organs. Yet, vaccines work by harnessing the capability of a fully competent immune system.

Since the FDA authorized the first COVID-19 vaccine, people with compromised immune systems have lived in limbo, waiting to find out whether, or how much, vaccination might protect them. The vaccine clinical trials excluded nearly all immune-compromised people because including them might interfere with determining vaccine effectiveness for the general population. But that’s left this group with little data on what vaccination means for them. Now studies are trickling in.

“We’re starting to learn some of the things we don’t know, whereas before, it was a bunch of we don’t know what we don’t know,” says Peter Martin, a hematologist and oncologist at Weill Cornell Medicine in New York City.

It’s difficult to gauge the number of immune-compromised people in the U.S. One study estimates that 2.8 percent of people with private insurance take immune-suppressing drugs—about nine million Americans. But that doesn’t include Medicare or Medicaid patients, who are more likely to have some conditions requiring immunosuppression, says study author Beth Wallace, a rheumatologist at University of Michigan Medicine. It also doesn’t include people with immune-compromising conditions who aren’t taking immune-suppressing medications.

From the very beginning of the pandemic Collins worried how her body would respond to the vaccine. But when she later read a study of organ transplant recipients that found low antibody levels after the first mRNA vaccine dose, she panicked.

Even though she had been vaccinated and wore a mask, she thought “How safe was I? It really scared me.”

A follow-up study that found about half of transplant recipients responded to the vaccine offered her little comfort. “That’s essentially the flip of a coin,” Collins says. But a small study published Monday offers a flicker of hope.

After two doses of mRNA vaccine, 30 transplant recipients with no or low antibodies got a third shot, though not necessarily of the same vaccine they received first. The six people with low antibody levels subsequently developed higher levels, and a quarter of the others, who had never responded to the COVID-19 vaccine, developed antibody levels thought to be high enough to prevent COVID-19 after the third dose.

But this study has substantial limitations: It’s very small and involves a grab bag of different vaccine combinations. Further, the Food and Drug Administration has not authorized a third dose, and the Centers for Disease Control and Prevention currently advises against it. The authors concluded that their findings suggest the need for more studies to test third doses in people without fully functioning immune systems.

A diverse population

Immune-compromised people fall into two broad categories: Either they have an underlying condition that weakens their immune system, such as people with leukemia, uncontrolled HIV, or a rare genetic disease, or they have an underlying condition requiring immune-suppressing therapy, such as organ transplant recipients and people with rheumatic diseases (inflammatory, autoimmune conditions) or some cancers. A few conditions, such as chronic lymphocytic leukemia and lupus, fall into both categories.

Factors that might affect someone’s response to a vaccine include the medication they’re taking and what it does, how long they’ve been taking it, their specific disease, and their history of infection. For organ transplant recipients, the time since their transplant may also matter.

“That’s why it’s really important for people who have these immune-suppressed conditions to talk to an expert about their specific situation, because there is such a great amount of variability,” says Aaron Richterman, an infectious disease fellow at the University of Pennsylvania Perelman School of Medicine, regarding how immune-compromised people can assess their infection risk after vaccination.

Evidence so far is mixed

The wide range of conditions and drugs that weaken the immune system explain why the response to COVID-19 vaccines is so mixed. The evidence so far shows that transplant recipients, certain leukemia patients, and people taking a handful of specific medications have the poorest vaccine response. The drugs that appear linked with the poorest response include mycophenolate (prevents organ rejection), rituximab (treats some blood cancers and autoimmune diseases like rheumatoid arthritis), belatacept (prevents organ rejection), and methotrexate (treats a wide range of cancers and autoimmune diseases).

For example, the organ transplant study Collins read found only 54 percent of 658 organ transplantrecipients had any antibodies after two doses of the mRNA vaccine, particularly if they were taking a drug like mycophenolate. A similar study of 609 kidney transplant recipients found half had detectable antibodies after mRNA vaccination, but only 5 percent of those taking belatacept did. Transplant recipients produced even fewer antibodies in response to the one-dose Johnson & Johnson vaccine.

Studies in people with autoimmune disease have similarly shown that vaccine response typically depends on the specific drug they’re taking.

In a study of 404 people with rheumatic disease who had both doses of an mRNA vaccine, almost all had detectable antibodies, but those taking rituximab or mycophenolate had very low levels. Meanwhile, everyone taking anti-inflammation drugs called tumor necrosis factor (TNF) inhibitors to treat Crohn’s disease or rheumatoid or psoriatic arthritis, had strong antibody responses.

Another study (preprint) of 133 people had similar findings: Antibody levels were 1/50 as high in people taking rituximab, a drug that intentionally depletes antibody-producing B cells, as in people with competent immune systems. Those taking certain chemotherapy drugs, rheumatoid arthritis drugs, or prednisone—a steroid that treats inflammation—also had lower antibody levels.

People with certain types of leukemia or lymphomas, particularly non-Hodgkin’s lymphoma and chronic lymphocytic leukemia, also don’t produce many antibodies after vaccination, though people with most other cancers fare better. That’s particularly concerning since some people with CLL don’t know they have it, says study author Mounzer Agha, director of the Mario Lemieux Center for Blood Cancers at University of Pittsburgh Medical Center.

Those are just a sampling of the studies examining different immunecompromising conditions and medications, but all are small, providing only some insight into these specific conditions or therapies.

“What matters is how much immunosuppression you’re getting, what agents you’re getting, and possibly how long you’ve been getting them,” says Dorry Segev, a transplant surgeon and researcher at Johns Hopkins Medicine who wrote the organ transplant studies and several others above.

More than just antibodies

These studies also focus only on antibody response, which is just one component of the immune response.

“We think antibody levels may correlate to clinical protection to a degree,” Richterman says. But even in healthy people, he says, we don’t know the minimum antibody levels necessary to assure protection. Since the significance of antibody levels is ambiguous, the FDA and CDC recommend against antibody testing because it is unclear how to interpret the findings.

“Immunologic responses and effectiveness of a vaccine are two different things,” says Emily Blumberg, director of Transplant Infectious Diseases at Penn Medicine in Philadelphia. “We think vaccinating [transplant] patients may have a benefit above and beyond what you can measure with antibodies.”

That’s partly because vaccines induce immunity in multiple ways. One way is stimulating B cells to make antibodies, which explains why medications that reduce B cells—such as rituximab, methotrexate, mycophenolate, and steroids—result in such poor responses. But vaccines can also stimulate killer T cells, which attack infected cells, and helper T cells, which aid B cells and killer T cells.

“Our understanding of what’s happening on the T cell side is pretty close to zero,” Segev says. Studying T cell responses is difficult and costly, he adds, though his group and others are working on it.

Vaccines can also trigger the production of memory B cells, which remember how to make antibodies. “If you get the virus and the memory cells are there, then you can have a better and faster antibody response the next time around,” explains Ignacio Sanz, chief of rheumatology at Emory University School of Medicine. He believes that presence of memory B cells might partly explain why a third vaccine dose led to antibody production in transplant recipients without previous responses.

The only way to find out how effective the vaccines actually are in immune-compromised people is to wait fordata comparing infections between vaccinated and unvaccinated people in different immune-compromised groups, and that takes time.

What comes next

Where does all this leave the millions of people who don’t know if they are protected by the vaccine, especially with the CDC’s advice that vaccinated people can stop masking?

For now, “get vaccinated, act unvaccinated,” Segev says. But that’s a difficult message to communicate.

“One of the unintended consequences of [that message] is fueling vaccine hesitancy in patients who say, ‘Why should I bother if I’m not going to have a response?’” Blumberg says.

A February study of more than 1,200 people with autoimmune disease found that more than half wanted to get vaccinated, and a third were uncertain, despite studies showing the vaccines are safe for those with inflammatory diseases.

Alfred Kim, a rheumatologist at the Washington University School of Medicine who conducted one of the studies on people with rheumatic disease, agrees it can be confusing to advise patients to get vaccinated without being able assure it protects them, but “even partial protection is better than no protection,” he says.

That introduces another problem: How safely can immune-compromised people go out in public even if vaccinated?

“The CDC guidelines assume everybody is socially responsible, which unfortunately is not the case,” Agha says.

“Masks work, but masks work best if everybody is wearing them,” Segev says. “If you have a superspreader walking around Kroger spewing their Delta variant all over the store, and they’re standing next to an immunosuppressed transplant patient who tried their best to get vaccinated and is still wearing a mask, that [immunosuppressed] person is still at risk.”

While immune-compromised patients have always been more susceptible to infections, even before the pandemic, the stakes are higher now.

“With influenza, it was not such a great concern because patients do survive influenza even when they get quite ill,” Mounzer says. “With COVID, it’s a different story. There’s a real risk of dying from the disease.”

In a post-masking world, that makes even brief trips to the grocery store more complicated—and perilous—for immune-compromised people.

“As a society I think we have an obligation to come up with strategies to prevent those people from getting acutely sick so they can re-enter society like the rest of us are all ready to do,” Martin, the hematologist, says. “They’re just as ready as anybody else, and it’s terrifying to be in their position.”

Blumberg tells her patients to encourage friends, family members, and coworkers to get vaccinated. “The better job we do with vaccinating everybody, the less COVID there will be to make them sick,” she says.

That’s exactly what Collins, the vaccinated transplant recipient from Texas, is doing. But she has friends and family members who refuse to get vaccinated, and that frightens her, not only for herself but also for other immune-compromised family members and friends.

“If we reach herd immunity, then I have less to worry about,” Collins says. But she doesn’t think the country will reach that milestone, “which is scary for people like me.”

If social responsibility does not motivate people to get vaccinated, there’s also the specter of new variants. Evidence suggests that people whose immune systems don’t respond properly to infection could provide an ideal environment for mutations, says John Moore, a microbiologist and immunologist at Weill Cornell Medicine in New York City. “They have a lot of ongoing viral replication in their bodies for prolonged periods of time,” Moore says. “Virus replication in an antibody-low individual can drive the emergence of variants that are problematic on a societal basis, so this is not a trivial issue.”

In other words, protecting the most vulnerable members of society is ultimately the best way to protect all of society.

“These are the patients that are going to be a source of continued infection in the population,” Blumberg says. “If we don’t protect these immuno-suppressed hosts, we will have a harder time getting rid of the virus.”

Third Dose of COVID Vaccine Boosts Protection in Transplant Recipients | Health News

Third Dose of COVID Vaccine Boosts Protection in Transplant Recipients | Health News

  • June 15, 2021

By Robert Preidt, HealthDay Reporter

(HealthDay)

TUESDAY, June 15, 2021 (HealthDay News) — Researchers say an extra dose of two-dose COVID-19 vaccines may improve immune system protection for organ transplant patients, a group that’s so far responded poorly to two-dose vaccines.

“Our findings suggest clinical trials are warranted to determine if transplant recipients should receive COVID-19 vaccine booster doses as standard clinical practice, similar to what is currently done with hepatitis B and influenza vaccinations for this population,” said study lead author Dr. William Werbel. He is an infectious diseases research fellow at the Johns Hopkins School of Medicine in Baltimore.

People who receive a heart, lung, kidney or other solid organ transplant often take drugs to suppress their immune system and prevent rejection, but those drugs can interfere with the body’s ability to make antibodies in response to vaccines.

In two previous studies, only 17% of transplant recipients produced sufficient antibodies after one shot of a two-dose COVID-19 vaccine, and only 54% produced sufficient antibodies after the second dose, researchers reported.

Even transplant recipients who produced antibodies had levels well below those typically seen in people with healthy immune systems, the findings showed.

In the new study, the researchers evaluated 30 transplant recipients who previously received two doses of either the Moderna or Pfizer/BioNTech vaccine. None had reported an illness or a positive test for SARS-CoV-2 prior to vaccination. All were taking multiple immunosuppressive medications to prevent organ rejection.

Between March 20 and May 10, all participants got a third dose of either one of the Moderna or Pfizer vaccines, or they got the Johnson & Johnson shot.

“A third of the participants who had negative antibody levels and all who had low positive [antibody] levels before the booster increased their immune response after a third vaccine dose,” said study senior author Dr. Dorry Segev. He directs the Epidemiology Research Group in Organ Transplantation at Hopkins.

A week after receiving their third dose, 23 patients completed a questionnaire and some reported generally mild or moderate side effects. One patient had severe arm pain and another reported a severe headache. No patients reported fever or an allergic reaction.

There was one case of mild organ rejection, according to the report published online June 15 in the Annals of Internal Medicine.

Segev said the reactions seem acceptable, given the benefits that vaccines can confer.

Meanwhile, Werbel urged transplant patients and other immunocompromised patients to be careful.

“Although the third vaccine dose appears to raise the immune response of transplant recipients to higher levels than after one or two doses, these people may still be at greater risk for SARS-CoV-2 infection than the general population who have been vaccinated,” he said in a Hopkins news release.

“Therefore, we recommend that transplant recipients and other immunocompromised people continue to wear masks, maintain physical distancing and practice other COVID-19 safety measures,” Werbel added.

The American Society of Transplantation has more on COVID-19.

SOURCE: Johns Hopkins Medicine, news release, June 14, 2021

Copyright © 2021 HealthDay. All rights reserved.

Health expert explains how COVID-19 vaccines strengthen immune system to fight the virus

Health expert explains how COVID-19 vaccines strengthen immune system to fight the virus

  • June 15, 2021

BIRMINGHAM, Ala. (WBRC) – When getting vaccinated for the COVID-19 shot, it can make you feel crummy for a couple days but doctors say that doesn’t mean your immune system is slacking.

Even if you experience side effects, doctors say the vaccine does not weaken your immune system, instead, it strengthens it.

COVID-19 vaccines strengthen the immune system’s response to the virus, and the body having chills or fatigue is your immune system ramping up its power.

“We know that immune response can vary,” explained ADPH’s Dr. Karen Landers.

The data supports the conclusion that getting the vaccine will lessen the potential of a really bad case of COVID if you’re one of the people to contract it after getting the shot.

“Persons are less likely to have a severe illness, less likely to be hospitalized and they are less likely to die,” said Dr. Landers.

The vaccine arms the immune system with fighters, but they don’t always win; 800 Alabama residents who got the vaccine, got COVID after.

“We’ve had 54 people hospitalized which is an exceedingly small number,” said Dr. Landers.

She says the shot is the only surefire way to give your body the tools to effectively ward off worse case-scenarios.

Breakthrough cases are usually identified in people who go to the doctor with symptoms, so if you do have symptoms go get tested.

Copyright 2021 WBRC. All rights reserved.

Study Reveals Recipe for Even More Powerful COVID-19 Vaccines | The Brink

Study Reveals Recipe for Even More Powerful COVID-19 Vaccines | The Brink

  • June 11, 2021

A new study looking at the way human cells activate the immune system in response to COVID-19 infection could open the door to even more effective and powerful vaccines against SARS-CoV-2 and the rapidly emerging variants keeping the global coronavirus pandemic smoldering.

Researchers from Boston University’s National Emerging Infectious Diseases Laboratories (NEIDL) and the Broad Institute of MIT and Harvard say it’s the first real look at exactly what types of “red flags” the human body uses to enlist the help of T cells—killers sent out by the immune system to destroy infected cells. Until now, COVID vaccines have been focused on activating a different type of immune cell, B cells, which are responsible for creating antibodies. Developing vaccines to activate the other arm of the immune system—the T cells—could dramatically increase immunity against coronavirus, and importantly, its variants.

In their findings, published in Cell, the researchers say current vaccines might lack some important bits of viral material capable of triggering a holistic immune response in the human body. Based on the new information, “companies should reevaluate their vaccine designs,” says Mohsan Saeed, a NEIDL virologist and the co-corresponding author of the paper.

Saeed, a BU School of Medicine assistant professor of biochemistry, performed experiments on human cells infected with coronavirus. He isolated and identified those missing pieces of SARS-CoV-2 proteins inside one of the NEIDL’s Biosafety Level 3 (BSL-3) labs. “This was a big undertaking because many research techniques are difficult to adapt for high containment levels [such as BSL-3],” Saeed says. “The overall coronavirus research pipeline we’ve created at the NEIDL, and the support of our entire NEIDL team, has helped us along the way.”

A photo of Mohsan Saeed working at a computer
Mohsan Saeed, BU NEIDL virologist, says the new findings could be a gamechanger for coronavirus vaccine design. Photo courtesy of Mohsan Saeed

Saeed got involved after he was contacted by genetic sequencing experts at the Broad Institute, computational geneticists Pardis Sabeti and Shira Weingarten-Gabbay. They hoped to identify fragments of SARS-CoV-2 that activate the immune system’s T cells. 

“The emergence of viral variants, an active area of research in my lab, is a major concern for vaccine development,” says Sabeti, a leader in the Broad Institute’s Infectious Disease and Microbiome Program. She is also a Harvard University professor of systems biology, organismic and evolutionary biology, and immunology and infectious disease, as well as a Howard Hughes Medical Institute investigator.

“We swung into full action right away because my laboratory had [already] generated human cell lines that could be readily infected with SARS-CoV-2,” Saeed says. The group’s efforts were spearheaded by two members of the Saeed lab: Da-Yuan Chen, a postdoctoral associate, and Hasahn Conway, a lab technician.

From the outset of COVID pandemic in early 2020, scientists around the world knew the identity of 29 proteins produced by SARS-CoV-2 virus in infected cells—viral fragments that now make up the spike protein in some coronavirus vaccines, such as Johnson & Johnson’s. Later, scientists discovered another 23 proteins hidden inside the virus’ genetic sequence; however, the function of these additional proteins was a mystery until now. The new findings of Saeed and his collaborators reveal—unexpectedly and critically—that 25 percent of the viral protein fragments that trigger the human immune system to attack a virus come from these hidden viral proteins.

How exactly does the immune system detect these fragments? Human cells contain molecular “scissors”—called proteases—that, when the cells are invaded, hack off bits of viral proteins produced during infection. Those bits, containing internal proteins exposed by the chopping-up process—like the way the core of an apple is exposed when the fruit is segmented—are then transported to the cell membrane and pushed through special doorways. There, they stick outside the cell acting almost like a hitchhiker, waving down the help of passing T cells. Once T cells notice these viral flags poking through infected cells, they launch an attack and try to eliminate those cells from the body. And this T cell response isn’t insignificant—Saeed says there are links between the strength of this response and whether or not people infected with coronavirus go on to develop serious disease.

“It’s quite remarkable that such a strong immune signature of the virus is coming from regions [of the virus’ genetic sequence] that we were blind to,” due to the fact that many researchers around the world were so focused on the coronavirus’ spike protein, but not the rest of the virus’ genetic code, says Weingarten-Gabby, the paper’s lead author and postdoctoral fellow in the Sabeti lab. “This is a striking reminder that curiosity-driven research stands at the basis of discoveries that can transform the development of vaccines and therapies.”

“Our discovery … can assist in the development of new vaccines that will mimic more accurately the response of our immune system to the virus,” Sabeti says.

T cells not only destroy infected cells but also memorize the virus’ flags so that they can launch an attack, stronger and faster, the next time the same or a different variant of the virus appears. That’s a crucial advantage, because Saeed and his collaborators say the coronavirus appears to delay the cell’s ability to call in immune help.

“This virus wants to go undetected by the immune system for as long as possible,” Saeed says. “Once it’s noticed by the immune system, it’s going to be eliminated, and it doesn’t want that.”

Based on their findings, Saeed says, a new vaccine recipe, incorporating some of the newly discovered internal proteins making up the SARS-CoV-2 virus, would be effective in stimulating an immune response capable of tackling a wide swath of newly emerging coronavirus variants. And given the speed with which these variants continue to appear around the world, a vaccine that can provide protection against all of them would be a game changer. 

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COVID-19: Can Mixing of Different Vaccines Boost Immune Responses?

COVID-19: Can Mixing of Different Vaccines Boost Immune Responses?

  • June 11, 2021

The usual vaccination scheme for COVID-19 has been to administer both doses of the same type of vaccine. Most of the vaccines authorised require two doses within a gap of a few weeks or months. However, some countries are experimenting with mixed doses as part of a new programme, which means that the people receive one shot from one vaccine and the other shot from another vaccine.

Canada and several other European countries are now recommending this mixed vaccine in some patients. Some early data coming out of such experiments have been published and they provide an early hint of probable benefits of such a policy.

In this context, three recent studies can be taken into consideration, where it has been found that having a dose of the Pfizer-BioNTech vaccine after one dose of the Oxford-AstraZeneca vaccine can elicit more efficient immunity. 

One study from Spain, published in Lancet, reported that 448 participants who received the Pfizer-BioNTech (PB) vaccine eight weeks after getting the Oxford-AstraZeneca (OA) dose showed robust antibody response when analysed after two weeks from the last dose. The study concluded that there were no serious adverse events registered among the participants. The antibody response was examined against the spike protein, a key protein of SARS-CoV-2 for infecting human cells. 

The other study is from Charité University Hospital, Berlin. Leik Eric Sander, an infectious disease expert of the University, along with his colleagues found that the 61 health care workers who were given the two shots in the same order as the study from Spain, showed antibodies against the spike protein at a comparable level with a control group who received two doses of the PB vaccine. The mixed vaccines were administered at a gap of 10 to 12 weeks. The study even reported having found that the T cells of those who received the mixed vaccines were better in comparison to those who got both doses of PB alone. Yet another study in Germany also showed comparable results.

Also read: Neutralising Antibodies Can be Marker of COVID-19 Vaccine Efficacy

However, there is a caveat. Mathew Snape, a vaccine expert at the University of Oxford, and his colleagues are now studying eight vaccine permutations and this study involves about 100 participants. Here as well, the OA and the PB vaccines are used in different permutations at an interval of either four or twelve weeks.

In May, Snape’s group published an early report in Lancet that when the participants received the PB vaccine after just four weeks of the OA vaccine, they showed significantly more side effects in comparison to those who received both the doses of the same vaccine type. However, the immune response data is yet to come out. 

Here arises another question—is it the mixing of vaccines or the dose intervals that is important in generating immunity? Snape, at this point put forward the view that the combination vaccines are showing promising results so far, however it is yet to be resolved whether any improvement in T cell response results from longer dose intervals rather than the mixing. 

A few countries, however, have recommended this combination vaccine, including Spain which has authorised it for people under the age of 60 years, Canada, Germany, France, Norway, and Denmark have also made similar recommendations. 

Talking about the practical applicability of mixed vaccines, eminent vaccine specialist and professor at Christian Medical College, Vellore, Gagandeep Kang told NewsClick, “Spain authorised the mixing of vaccines after it made the decision not to use the AstraZeneca vaccine in younger individuals. The data from the CombiVacS study indicates that the immune responses with the mixing of doses are better than if two doses of the AstraZeneca vaccine are used. This is reassuring data that supports the use of vaccines in a mixed schedule. ”

She added, “For immunisation programmes, particularly in developing countries and when supplies are limited, it is very useful to know if the vaccines can be mixed. Wherever the delivery of vaccines is challenging, or if people are inconvenienced or find it difficult to access a vaccination centre, then making sure that any vaccine that is available at a vaccination centre can be given to all attendees is particularly valuable.”

Also read: How Getting a Vaccine in India Is a ‘Privilege’ Especially For Those in Rural Areas

Prof Satyajit Rath, adjunct faculty at IISER, Pune, had a similar view. He said, “They certainly have real-life utility. As we know, inadvertent ‘mixing’ can happen, and it is good to know what the consequences would be. Also, since the supply of any one vaccine can be erratic especially because the huge scale of the COVID-19 vaccination program, it is useful to know if such ‘mixing’ can be done safely and usefully. And finally, there may even be some modest but real advantages to some such ‘mixed’ protocols in specific situations, and it would be useful to have evidence about that possibility, too.”

On being asked whether mixing two types of vaccines can give the immune system multiple ways to recognise a pathogen (generally, it is said that mRNA vaccines are good at inducing antibody responses while vector-based vaccines are better at triggering T cell responses), Kang said, “Yes, mixing two types of vaccines gives the immune system multiple ways to recognise a pathogen. It may be possible to combine two different vaccination platforms where we can ensure both early and high levels of short-term and long-term protection.”

“However,” she added, “in the immunogenicity studies that are planned, we will only have the immunogenicity readouts and not a measure of the protection afforded by mixed schedules at this time. Since samples will be banked, when we have a correlate of protection, it may be possible to interpret the data from mixed schedules for protection as well.”

Another important question is if the idea is at all implementable, then what would matter the most – the types of vaccine or the duration between the doses or the order in which the doses are applied or a combination of all of these?

Also read: COVID-19: Vaccination Experiment in a Brazilian Town Reveals Surprising Results

Prof. Kang explained, “For scheduling patients for immunisation it is important to know which types of vaccines are to be given to which individuals and at what time points. A fully flexible schedule, where any vaccine can be given or in any schedule is the ideal. If the immunogenicity studies show that the ordering of vaccines, i.e. which one goes first and which one is next, or differences in intervals between doses, make significant differences to the immune response, then it becomes somewhat more challenging to implement the programme.”

Even if several countries have recommended the mixing of vaccines, there remains a crucial aspect; that is what should be the premise if a country plans to start such a mixed vaccine experiment?

Talking about it, Rath told NewsClick, “All such ‘experiments’ have to be formal clinical trials, more or less at the level of a phase 1-2 clinical trial. The premise would be that ‘mixed’ protocols would give rise to at least as much of an antibody response as the approved single-vaccine protocols would (and possibly more!).”

Suggesting measures that can be adopted in India, Kang said, “I think it is very important for all countries that are using multiple vaccine platforms to understand how different combinations are likely to work. It is not required that every country should do its own mix and match schedules as studies, if data on the same vaccine combinations are available from other countries.”

She further said that, “For India, where many of the vaccines being used are likely to be made by Indian manufacturers, it is important that we initiate these studies as early as possible, to inform our own immunisation programme and also when Indian vaccines are exported, make these data available for the world.”

The next generation Covid-19 vaccines seeking a slice of the market

The next generation Covid-19 vaccines seeking a slice of the market

  • June 11, 2021

A new group of vaccine makers is hoping to challenge the Covid-19 shots that are already household names, sharpening competition in what is set to be the first ever jab market to encompass the entire global population.

BioNTech/Pfizer and Moderna, the pandemic’s mRNA-based vaccine frontrunners, have already booked billions of dollars in revenue, which they are using to boost production, sign new contracts and entrench their positions. Likewise, Oxford/AstraZeneca and Johnson & Johnson have been rolling out their cheaper and easier to transport shots for months, while Chinese and Russian-made vaccines dominate in several markets.

Yet the global need for coronavirus vaccines is so great that the pandemic’s next phase provides a chance for other players to break in. Large pharma companies like Sanofi and GSK are hoping to shake off their image as laggards, while start-ups such as Novavax, CureVac and Valneva see opportunities to satisfy unmet needs.

The newcomers face particular hurdles: emerging variants damping the efficacy rates in clinical trials, production capacity eaten up by already approved shots, and a public that may be more inclined to trust the vaccines they know. 

But the size of the opportunity to provide doses, both for initial inoculations and potential booster shots, makes it worthwhile. Indeed, newcomer Novavax is forecast to overtake Moderna as the second-largest Covid-19 vaccine maker by revenue next year, with estimated sales of $17.9bn in 2022, according to Airfinity, a London-based analytics company. And if their vaccines are approved, it predicts Sanofi, GSK, and CureVac will all book more than $6bn in sales next year, far more than the $1bn in annual revenue that typically defines a “blockbuster” drug.

“When you make a product essentially everyone in the world wants or needs, you are going to make a lot of money,” said Walid Gellad, director of the centre for pharmaceutical policy and prescribing at the University of Pittsburgh.

Vaccine makers to grow Covid-19 jab revenue in 2022, forecast revenue ($bn)

The new challengers

Many of the prospective new vaccines heading for regulatory approval are not based on more innovative technologies. Several are more traditional shots, like the jab under development at GSK and Sanofi, that were leapfrogged by 2020’s breakthrough mRNA jabs. 

But some may have advantages, including, in the case of CureVac’s jab, being cheaper to produce and possibly easier to combine with other vaccines in a single shot. The Valneva vaccine, meanwhile, may elicit a better immune response from the elderly. 

Novavax

A Maryland-based start-up with a tortuous 33-year journey to its first vaccine, Novavax is likely to be the first of this second wave of shots to win approval. Many scientists like its traditional protein-based jab, which has an unusual production method — its proteins are grown in moth cells — and a proprietary adjuvant, which boosts the body’s immune response to the vaccine. 

The shot was created and trialled alongside the first wave of vaccines, proving 89 per cent effective against the original strain of coronavirus. But it has taken longer for the company to scale production.

“We’re the 1.5, last of the first generation,” said Greg Glenn, head of research and development at the biotech. The company expects to apply for approval in the third quarter and Glenn said the jab, which could be stored long term in a refrigerator, would “contribute in a major way to the unmet need” for doses across the globe. 

Sanofi and GSK

The large vaccine manufacturers Sanofi and GSK, despite failing to keep up with likes of Pfizer last year, are also expected to play an important role supplying middle- and lower-income countries with their co-developed protein-based vaccine. The companies were forced to redo their phase 2 trial, eventually showing a strong immune response after a dosing mistake. But their existing production capacity and the potential to distribute the shot alongside other vaccines, like the flu jab where Sanofi is dominant, could mean they eventually play a bigger role. 

Valneva

The French vaccine maker, which has a large deal with the UK government because of its Scottish production facilities, is using one of the oldest vaccination technologies: a whole inactivated virus. It says this could be an advantage against variants when compared with those vaccines that only use the spike protein, as it should enable the body to recognise other proteins in Sars-Cov-2 if the spike mutates significantly. The company, which has started its phase 3 trial, also believes the adjuvant it uses to boost the immune response to the vaccine may make the shot more effective in older people or the immunocompromised.

At Valneva in France, scientists have used a whole inactivated virus to build a vaccine that they say could perform better that other shots against new strains of Covid-19 © David Vincent/AP

Thomas Lingelbach, Valneva chief executive, said it was aiming to produce 150m to 200m doses a year. “Of course we are not going to be the ones to produce billions of doses. That has never been our intent. We will look at target populations and settings where we can contribute, not where we will lead.” 

CureVac

The next round of vaccines could also introduce a third mRNA shot to the market. CureVac, the German biotech, believes its different formulation will give it advantages over the Pfizer and Moderna shots.

By requiring a much lower dose, its cost of production is relatively low and it could be easier to combine vaccines targeting different variants in a single shot. CureVac’s scientists also believe that by not making any chemical modifications to the mRNA the shot may be able to elicit a stronger response from the body’s T-cells, which supplement antibodies in the immune system.

Pierre Kemula, CureVac’s chief financial officer, believes these factors will be important selling points once the pandemic is more under control. “Lower dose, decent cost of goods, broader solution mix of large, mid and small scale production and flexibility. It will be really interesting to see what this can bring to the world.”

Beyond the needle

Other vaccine developers still in the race are smaller and generally less advanced, but are testing new technologies or novel delivery mechanisms that they hope will make the difference.

ImmunityBio

The California-based biotech founded by billionaire Patrick Soon-Shiong is testing four delivery methods for its new vaccine — a jab, capsule, pill to take under the tongue, and a nasal spray. ImmunityBio, which has a market capitalisation of $6.2bn and focuses on cancer treatments, hopes its viral-vector vaccine, which stimulates T-cells and is currently in phase 1 trials, will deliver longer-lasting immunity. 

“There’s always going to be Pfizer, Moderna, J&J, AstraZeneca, and there should be, but will that be enough for the world?” said Soon-Shiong, who also owns the LA Times newspaper.

The California-based ImmunityBio founded by billionaire Patrick Soon-Shiong is testing four delivery methods for its new vaccine — a jab, capsule, pill to take under the tongue, and a nasal spray © David Paul Morris/Bloomberg

Vaxart

Vaxart, another Californian biotech, is creating oral vaccines that could be easier to administer, particularly in lower and middle income countries. In Vaxart’s phase 1 study, the company said its coronavirus vaccine tablet elicited higher T-cell responses than those seen in people who had received Pfizer and Moderna’s jabs.

Vaxart’s vaccine aims to induce immunity in the nose and mouth. “You swallow the tablet, it gets into your intestine, makes the protein of interest [then] tricks your body into thinking it’s been infected and makes an immune response,” said Sean Tucker, founder and chief scientific officer.

Medicago

Other companies, such as Medicago, the Canadian vaccine maker that is also partnering with GSK for its adjuvant, are hoping to differentiate themselves with their production methods. Medicago grows its vaccine proteins in a plant from the tobacco family, mashing up the leaves into a smoothie to extract what it needs, bypassing the struggles vaccine makers often face when scaling up in animal cells.

For some of these smaller companies, even crumbs from the table could be big profit generators. Olga Smolentseva, equity analyst at investment bank Bryan, Garnier & Co, said she expected mRNA vaccines to dominate in the developed world but that smaller players could still end up with a slice significant for their size. “The scale of the game is different,” she said. 

The booster market

For many of these companies, much will depend on whether we require boosters every six months, every year, every few years or never, and whether shots will have to be tailored to tackle variants.

Pfizer’s chief executive Albert Bourla has said a booster shot will probably be needed within 12 months. Many vaccine makers are conducting their own studies of boosting the immunity of participants of their early trials, with seven participating in the UK’s CoV-Boost study. 

More than 23bn Covid-19 vaccine doses could be produced next year, Covid vaccine production forecast for 2022, number of doses (bn)

But so far, there is no scientific consensus on how long immunity lasts. Evidence based on recovering from Covid-19, not vaccination, looks promising. A limited study, conducted by University College London, found that exposure to Covid-19 substantially cut the risk of reinfection — up to 85 per cent — among care home residents and staff for up to 10 months.

Ian Jones, a professor of virology at the University of Reading, said the study added to existing evidence that showed bone marrow cells that make protective antibodies against Covid-19 could be found in patients for up to a year following infection.

“If the same is true of vaccinated individuals, which seems likely, boosters may not be needed as frequently as has been supposed,” he said. 

The Maryland-based start-up Novavax is forecast to overtake Moderna as the second-largest Covid-19 vaccine maker by revenue next year, with estimated sales of $17.9bn in 2022 for its traditional protein-based jab © Karen Ducey/Getty

If the virus continues to mutate that equation could still change. Most vaccines appear to offer protection against the emerging variants but some studies have shown reduced efficacy in response to the Beta and Delta strains, which first emerged in South Africa and India respectively.

Pfizer and Moderna completed their trials while the original Wuhan strain was still dominant, so their top line results may always look better than rivals contending with the new mutations. As a result CureVac is trying to moderate expectations before publishing its data, with Kemula saying efficacy of 70 per cent against even mild infection would be “absolutely great”.

Prices and profits

Clay Heskett, a partner who leads LEK Consulting’s European life sciences practice, said the dominance of the big four vaccines — Pfizer, Moderna, AstraZeneca, and J&J — would make them hard to displace, at least until vaccination brings infection rates down. “It will be tough to knock those four vaccines off the perch,” he said.

Pfizer and Moderna could use the “windfall of having been first to market, with incredible uptake and frankly cash flow” to ensure a huge production scale that should enable them to price competitively in years to come, Heskett said. Pfizer’s vaccine is forecast to generate $35.8bn in revenues in 2022, almost twice as much as the second-largest player.

The first generation of vaccine developers had to battle to scale up manufacturing but now have a stranglehold on some key vaccine inputs. Valneva’s Lingelbach said suppliers would not prioritise his company because its vaccine was not approved, even as he tried to scale up from 20 per cent to full capacity. “Thus far, we have been living from hand to mouth on raw materials,” he said. 

Few of the newcomers want to discuss undercutting their rivals but as supply increases, eventually vaccine makers may have to compete on price.

CureVac’s Kemula says he sees a sweet spot between the “rock bottom” prices of a non-profit vaccine like the J&J shot and the higher priced Moderna and Pfizer mRNA jabs.

John Grabenstein, president of consultants Vaccine Dynamics, agreed there remained much to play for. He is still tracking 12 vaccines with significant potential, including Valneva and CureVac, down from the 300 projects he started watching in early 2020.

“The second wave may not get the $20 a dose vaccines but they will get the $10 a dose market,” he said. “And the volumes are so huge, orders of magnitude above what we think a big volume vaccine market is.”

Additional reporting by Erika Solomon in Berlin

Mixing COVID-19 vaccines appears to boost immune responses | Science

Mixing COVID-19 vaccines appears to boost immune responses | Science

  • June 9, 2021

Initial data support giving a dose of AstraZeneca’s COVID-19 vaccine (left) followed by one of Pfizer and BioNTech’s (right).

Victoria Jones/PA Images via Getty Images

Science’s COVID-19 reporting is supported by the Heising-Simons Foundation.

Faced with short supplies of COVID-19 vaccines and unforeseen side effects, some countries have adopted an unproven strategy: switching shots midstream. Most authorized vaccines require two doses administered weeks or months apart, but Canada and several European countries are now recommending a different vaccine for the second dose in some patients. Early data suggest the approach, born of necessity, may actually be beneficial.

In three recent studies, researchers have found that following one dose of the vaccine made by AstraZeneca with a dose of the Pfizer-BioNTech vaccine produces strong immune responses, as measured by blood tests. Two of the studies even suggest the mixed vaccine response will be at least as protective as two doses of the Pfizer-BioNTech product, one of the most effective COVID-19 vaccines.

Only a few of the potential vaccine combinations have been tested. But if mixing vaccines proves safe and effective, it could speed the effort to protect billions of people. “This possibility opens new perspectives for many countries,” says Cristóbal Belda-Iniesta, a clinical research specialist at the Carlos III Health Institute. Governments, for example, could immediately distribute new doses without worrying about setting aside second shots of specific vaccines to give people weeks or months later.

Europe and Canada have an added incentive. Millions of people there received an initial dose of the AstraZeneca vaccine before governments recommended younger age groups avoid it because of the risk of a rare clotting disorder. They were left wondering what to do next: Get a second dose or switch to a different vaccine?

In a Spanish study that Belda-Iniesta helped lead, 448 people who received a dose of the Pfizer-BioNTech vaccine 8 weeks after an initial AstraZeneca dose had few side effects and a robust antibody response 2 weeks after the second shot. All 129 blood samples tested could neutralize a noncoronavirus expressing spike, the SARS-CoV-2 surface protein key to infecting cells, he and colleagues reported last month on The Lancet’s preprint site.

Similarly, Leif Erik Sander, an infectious disease expert at the Charité University Hospital in Berlin, and colleagues found that 61 health care workers given the two vaccines in the same order, but 10 to 12 weeks apart, produced spike antibodies at levels comparable to a control group that received two doses of Pfizer-BioNTech at the standard 3-week interval, and had no increase in side effects. Even more encouraging, their T cells, which can boost the antibody response and also help rid the body of already infected cells, responded slightly better to spike than fully vaccinated Pfizer-BioNTech recipients. A team conducting a smaller study in Ulm, Germany, had comparable results. Both groups have posted preprints on the medRxiv server.

“Two different vaccines may be more potent than either vaccine alone,” says Dan Barouch of Beth Israel Deaconess Medical Center, who helped develop the one-dose COVID-19 vaccine made by Johnson & Johnson. It and the two-dose AstraZeneca vaccine use a nonreplicating adenovirus as a “vector” to introduce DNA coding for the spike protein of SARS-CoV-2 into the recipient’s cells. Vaccines from Pfizer-BioNTech and Moderna instead use messenger RNA (mRNA) coding for spike, which cells take up and use to make the protein.

Mixing the two types of vaccine may give the immune system multiple ways to recognize a pathogen. “The mRNA vaccines are really, really good at inducing antibody responses, and the vector-based vaccines are better at triggering T cell responses,” Sander says. Matthew Snape, a vaccine expert at the University of Oxford, agrees the combination vaccine results so far are promising but cautions they don’t resolve whether any improvement in T cell response results from longer dose intervals rather than the mixing.

The recent studies are imperfect because they are not designed to assess actual protection against COVID-19. That would require following large groups receiving different vaccine combinations to see who gets infected and sick over many months. The antibody and T cell measurements the studies rely on are thought to correspond to real-life protection, but studies are ongoing to determine exactly how reliable these correlates are.

Still, the findings support recent policy changes. Spain has authorized the mixing of the two vaccines for people under age 60. Other countries that have put age limits on the AstraZeneca vaccine, including Canada, Germany, France, Norway, and Denmark, have made similar recommendations.

More data are expected in the coming weeks. Snape and colleagues are studying eight vaccine permutations in roughly 100 people each: a first dose of either AstraZeneca or the Pfizer-BioNTech vaccine, followed by a dose of either the same vaccine or the opposite, with intervals of either 4 or 12 weeks. The group reported in The Lancet last month that people who received the mRNA vaccine just 4 weeks after AstraZeneca’s suffered significantly more side effects than those who received two doses of the same vaccine; data on those subjects’ immune response are pending. The program has expanded to include second doses of Moderna’s mRNA vaccine and the Novavax vaccine, which delivers the spike protein directly.

As the world races to vaccinate as many people as possible against COVID-19, these combination studies could be one more weapon against the “just really embarrassing” inequality in global vaccine access, says Hugo van der Kuy, a clinical pharmacologist at Erasmus Medical Center. It will be important to also include vaccines widely used outside Europe, he says, such as those made by the Chinese companies Sinovac and Sinopharm, which rely on inactivated copies of SARS-CoV-2, and Russia’s Sputnik V, whose two doses each use a different adenovirus.Snape agrees. Mixing shots, he says, “will be the reality for many countries around the world aiming to make best use of the vaccines available to them.”

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