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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

Pfizer COVID-19 Vaccine Protective Against SARS-CoV-2 Variants (Medicine)

The Pfizer COVID-19 vaccine is protective against several SARS-CoV-2 variants that have emerged, according to new research presented this week in the journal mBio, an open-access journal of the American Society for Microbiology. While this is good news, the study also found that the only approved monoclonal antibody therapy for SARS-CoV-2 might be less effective against SARS-CoV-2 variants in laboratory experiments.
“The vaccines provide very strong protection against the earlier forms of the virus as well as the newer variants. This is an important point because I have heard people say that they don’t think there is a reason to get vaccinated, because the vaccine isn’t going to work against the variants, but that is not true—the vaccine will work against the variants,” said Nathaniel “Ned” Landau, Ph.D., professor in the Department of Microbiology at the NYU Grossman School of Medicine, in New York City.
To conduct their research, Dr. Landau and colleagues in the NYU Department of Microbiology and NYU Langone Vaccine Center created a panel of pseudotype viruses that combined the HIV virus and SARS-CoV-2 spike protein. Pseudotype viruses are replication-defective viral particles formed with a structural and enzymatic core from one virus and the envelope glycoprotein of another, that have been proven to be useful as research tools with little associated risk. “The  SARS-CoV-2 spike protein is important, because it is the only structure on the virus that is exposed to the outside. The spike protein is what sticks out from the virus; it is what the immune system recognizes and what allows the virus to stick onto target cells,” said Dr. Landau.
There are 2 reasons the researchers chose HIV to create their chimeric viruses. First, HIV is not particular about incorporating the HIV spike protein; it will take most any virus spike protein. Second, the HIV virus has been engineered to carry 2 reporter genes that allow researchers to study virus entry, antibody binding, and antibody neutralization.  When the virus infects a cell, the cell turns green and produces luciferase, the enzyme that makes fireflies light up at night. This provides a quick and easy way to count how many cells have been infected. “The spike protein-pseudotyped lentiviruses are extremely useful experimental tools. They were developed in the course of HIV research. They are less biohazardous and easier to work with in the lab,” said Dr. Landau.
The researchers created a panel of pseudotype viruses using the spike proteins from 6 different variants of SARS-CoV-2: the B.1.1.7 lineage variant identified in the United Kingdom, the B.1.351 lineage variant identified in South Africa, the B.1.1.248 lineage variant identified in Brazil, the COH.20G/677H lineage variant identified in Columbus Ohio, the 20A.EUs variant identified in Spain and later found elsewhere in Europe, and the Mink cluster 5 spike proteins located in minks in Denmark. They then mixed these pseudotype viruses with serum from either people who had received the Pfizer SARS CoV-2 vaccine or people who had already had COVID-19.
The researchers found that convalescent sera neutralize pseudotyped viruses with the 6 variants with only a small loss in titer. They also found that the Pfizer BNT162b2 vaccination worked just as well against the majority of variants as the earlier virus, but the  vaccine neutralized the South African variant and the Brazil variant with a 3-fold decrease in titer, an effect attributable to the mutation E484K. Dr. Landau said that people should not be concerned about these results, however.
“Our interpretation of the results is that the vaccine antibodies are very powerful, and even if you lose 3-fold of the titer, there is still plenty of antibody there to neutralize the virus. We believe the findings demonstrate that the vaccines will remain protective against the variants that we tested,” said Dr. Landau. “While it’s not reported in this paper, we have done the same experiments with the Moderna vaccine and got similar results.”
In another experiment, the researchers tested Regeneron Pharmaceuticals REGN-COV2, a  2 recombinant monoclonal antibody cocktail consisting of casirivamab and imdevimab, that has been effective at decreasing symptoms of individuals with COVID-19 and keeping them out of the intensive care unit. The researchers found that casirivamab had lost some of its neutralizing activity against the South African and Brazilian variants and the cocktail was 9- to 15-fold decreased in titer.
“One of the Regeneron antibodies is affected by the E484K mutation, and as a result the cocktail loses some of its neutralizing activity,” said Dr. Landau. “The question with this work is ‘how do  the laboratory findings translate into clinical effects, that is what will happen when you treat a patient infected with one of the variants?’ We cannot say for sure. We will only know when the clinical data comes in.”

DOI: https://doi.org/10.1128/mBio.00696-21

Provided by American Society for Microbiology

Significant Reductions in COVID-19 Infections Found After Single Dose of Oxford-AstraZeneca & Pfizer-BioNTech Vaccine (Medicine)

COVID-19 infections fell significantly – by 65% percent – after a first dose of the Oxford-AstraZeneca or Pfizer-BioNTech vaccines in this large community surveillance study.

Data from the COVID-19 Infection Survey, a partnership between the University of Oxford, the Office of National Statistics (ONS) and the Department for Health and Social Care (DHSC), is the first to show the impact of vaccination on antibody responses and new infections in a large group of adults from the general population aged 16 years and older.

Two studies, released today as pre-prints, focused on the protection from infection provided by COVID-19 vaccines. Researchers analysed 1,610,562 test results from nose and throat swabs taken from 373,402 study participants between 1 December 2020 and 3 April 2021. 21 days after a single dose of either Oxford-AstraZeneca or Pfizer-BioNTech vaccines (with no second dose), the rates of all new COVID-19 infections had dropped by 65%, symptomatic infections by 72% and infections without reported symptoms by 57%.

Reductions in infections and symptomatic infections were even greater after a second dose (70% and 90% respectively), and were similar to effects in those who had previously been infected with COVID-19 naturally. Vaccines were effective against variants compatible with the Kent strain (B.1.1.7). Benefits from vaccines in reducing new infections were similar in older individuals over 75 years and under 75 years, and in those reporting long-term health conditions and not reporting them.

Dr Koen Pouwels, senior researcher in Oxford University’s Nuffield Department of Population Health, says, ‘The protection from new infections gained from a single dose supports the decision to extend the time between first and second doses to 12 weeks to maximise initial vaccination coverage and reduce hospitalisations and deaths.

‘However, the fact that we saw smaller reductions in asymptomatic infections than infections with symptoms highlights the potential for vaccinated individuals to get COVID-19 again, and for limited ongoing transmission from vaccinated individuals, even if this is at a lower rate. This emphasises the need for everyone to continue to follow guidelines to reduce transmission risk, for example through social distancing and masks.’

The second study compared how antibody levels changed after a single dose of either Oxford-AstraZeneca or Pfizer-BioNTech vaccines, or two doses of the Pfizer-BioNTech vaccine (generally given 21-42 days apart). In individuals who had not had COVID-19 before, antibody responses to a single dose of either vaccine were lower in older individuals, especially over 60 years. Antibody responses to two Pfizer-BioNTech doses were high across all ages, particularly increasing responses in older people to reach similar levels to those receiving a single dose after prior infection.

Antibody levels rose more slowly and to a lower level with a single dose of Oxford-AstraZeneca vs Pfizer-BioNTech, but then dropped more quickly with a single Pfizer-BioNTech dose to similar levels as a single dose of Oxford-AstraZeneca, particularly at older ages. However, although the size of the immune response differed, there was no group of individuals who didn’t respond at all to either vaccine.

David Eyre, Associate Professor at the Big Data Institute at the University of Oxford, says, ‘In older individuals, two vaccine doses are as effective as prior natural infection at generating antibodies to the SARS-CoV-2 virus that causes COVID-19 – in younger individuals a single dose achieves the same level of response. Our findings highlight the importance of individuals getting the second vaccine dose for increased protection.’

Sarah Walker, Professor of Medical Statistics and Epidemiology at the University of Oxford and Chief Investigator and Academic Lead for the COVID-19 Infection Survey, says, ‘Without large community surveys such as ours, it is impossible to estimate the impact of vaccination on infections without symptoms – these have the potential to keep the epidemic going, particularly if people who have been vaccinated mistakenly think they cannot catch COVID-19. However, these studies show that vaccination and previous infection both protect against getting infected again.

‘We don’t yet know exactly how much of an antibody response, and for how long, is needed to protect people against getting COVID-19 in the long-term – but over the next year, information from the survey should help us to answer these questions. We are very grateful to all our participants for giving up their time to help us.’

Health Secretary Matt Hancock says, ‘Vaccines work and today’s findings from the ONS and Oxford University provide further evidence that both the Pfizer and AstraZeneca vaccines are having a significant impact on reducing infections across the UK.

‘With over 33 million first jabs already in arms, saving lives and cutting the risk of infection, it’s vital everyone gets their second dose when invited, to protect you and your loved ones against this disease. The vaccine programme has shown what our country can achieve when working as one, it is our way out of the pandemic. When you get the call, get the jab.’

Health Minister Lord Bethell says, ‘Studies like the ONS COVID-19 Infection Survey are critical to helping us build a picture of COVID-19 infections across the UK and I thank all those who took part and conducted this vital research.

‘These real-world findings are extremely promising and show our historic vaccination programme is having a significant impact across the UK by reducing infections among people of all ages, including those with underlying health conditions.

‘I urge everyone to take-up the offer of a free vaccine when invited and to make sure they get their second dose to gain maximum protection. It remains essential everyone continues to follow COVID-19 restrictions whether they have had the vaccine or not.’

The study will continue monitoring the pandemic in the UK on a weekly basis to look for early warning signs of rising infection rates in different regions, sub-regions, and demographic groups, and to continue to compare the effectiveness of different vaccines and to monitor the impact of immunity on protection against COVID-19.

Featured image: COVID-19 Infections Survey reveals similar, significant reductions in COVID-19 infections with single dose of Oxford-AstraZeneca and Pfizer-BioNTech vaccine. Image credit: Shutterstock

Provided by University of Oxford

How COVID-19 Vaccines will Get from the Factory to Your Local Pharmacy? (Medicine)

Bahar Aliakbarian is an expert in supply chain management in pharmaceuticals and a professor at the School of Packaging at Michigan State University. Below, she describes the vaccine supply chains of Pfizer and Moderna, which are expected to be the two major early suppliers of the COVID-19 vaccines in the U.S. She also talks about challenges in distribution and the work being done to ensure safe and systematic delivery of the vaccines.

What are the main challenges in distributing the newly developed COVID-19 vaccines?

The two major U.S. developers of the early COVID-19 vaccines are Pfizer/BioNTech and Moderna. They both developed mRNA vaccines, a relatively new type of vaccine. A major supply chain issue is the temperature requirement for these vaccines. The Pfizer vaccine needs to be stored at between minus 112 F (minus 80 C) and minus 94 F (minus 70 C), and the Moderna vaccine needs temperatures around minus 4 F (minus 20 C), which is close to the temperature of commercial-grade freezers. A third company developing vaccines, AstraZeneca, says it needs regular refrigeration temperature of 36 F to 46 F, or 2 to 8 C.

Moderna’s vaccine can remain at minus 4 F for up to six months, and then for a month in a refrigerator, according to the companyPfizer says its vaccine has a shorter shelf life of five days after being transferred from ultracold storage to a refrigerator, leaving a short window to administer the vaccines.

Temperature requirements for the Pfizer/BioNTech, Moderna, and AstraZeneca COVID-19 vaccines. The Conversation US, CC BY-ND

How will these vaccines be transported and stored?

Moderna plans to use an approach similar to that used in previous outbreaks such as the H1N1 swine flu pandemic in 2009. In this case the vaccines will be shipped from the manufacturing facilities in the Northeast U.S. and Europe to a distribution center in Irving, Texas, which will be equipped with freezers to store the vaccine for longer periods. From there they are distributed to hospitals, pharmacies and other vaccine administration sites.

Pfizer is manufacturing its vaccines in Kalamazoo, Michigan. It will handle the transportation to the administration sites by working with logistics partners. Because ultracold storage is available only at large facilities and hospitals, that’s where they’ll be stored for short periods before being distributed to administration sites.

Some states, like New York, are considering setting up their own distribution hubs.

Moderna and Pfizer/BioNTech use different distribution strategies because of different requirements for their vaccines, and Moderna’s participation in Operation Warp Speed. The Conversation US, CC BY-ND

How will the required temperatures be maintained?

Pharmacies and hospitals are trying to develop or acquire ultralow-temperature freezers, but it is a huge cost for them. We’re now seeing extremely high demand for freezers and dry ice, and there is risk of shortage. So the vaccines need to be supplied and administered efficiently to ensure they reach the public without any waste or bottlenecks in the supply chain. In 2019 alone, around US$34 billion worth of vaccines were wasted because of fluctuations in temperature during transportation.

Dry ice is used to maintain ultralow temperatures required to store the vaccines. The Conversation US, CC BY-ND

Dry ice is an inexpensive way to maintain low temperatures. Pfizer’s suitcaselike “thermal shippers” need about 50 pounds of dry ice to keep them at temperature for a few days. It is considered to be a hazardous material in planes, but the Federal Aviation Administration has granted permission to use up to five times the normally permitted amount to be transported along with the vaccines.

The staff at administration sites must be trained to check the temperature and make sure that Pfizer’s thermal box is not being opened more than a few times a day, not more than a few minutes at a time, and to fill it with new dry ice at the right times. Some of this training is already underway.

What can be done about monitoring and traceability?

Tracking and monitoring them throughout the process ensures that the vaccines are stable and not tampered with. Making this data accessible to governments and the public can increase trust in the vaccines. This is especially important because these vaccines require two doses to work, and we need people to come back to get the second one, and to follow up with them for feedback about any possible adverse effects.

My team and I are working on developing technologies to improve tracking and monitoring using smart packaging by implementing sensors and other communication technologies

Monitoring and tracking also involves developing databases that integrate data within an end-to-end supply chain, from the manufacturers to the administration sites. Right now, Pfizer and Moderna will have the information until it reaches the administration sites, and the hospitals and pharmacies will have the data about the patients though electronic health records (EHR). So there are some challenges we are still trying to overcome to have an integrated and interoperable system with improved capability to be upgraded and used nationwide.

Insurance companies and the government are thinking about how to provide coverage for the vaccines while the Centers for Disease Control and Prevention issues guidelines to ensure that most of the population receives the vaccine efficiently.

This article is republished from The Conversation under a Creative Commons license. Read the original article.