Tag: COVID vaccine

Vaccine Acceptance is Increasing Around the World

Image of a syring for vaccination
Photo by Mika Baumeister on Unsplash

COVID vaccine acceptance across much of the world increased by 3.7% between 2020 and 2021, according to a new study published in Nature Communications.

In a June 2021 survey of over 23 000 individuals across 23 countries, the researchers found that 75.2% of respondents reported vaccine acceptance, up from 71.5% one year earlier.  

The study was carried out during a year of substantial but very unequal global COVID vaccine availability and acceptance, which required new assessments of the drivers of vaccine hesitancy and the characteristics of people not vaccinated.

Vaccine hesitancy was most consistently associated with concerns about vaccine safety and efficacy and mistrust in vaccine development. Other factors associated with vaccine hesitancy varied by country and included personal experience with COVID (eg, sickness or loss of a family member) and demographic characteristics (eg, gender, education, and income).

The authors also found that vaccine hesitancy was not associated with a country’s current COVID case burden and mortality. In June 2021, vaccine hesitancy was reported most frequently in Russia (48.4%), Nigeria (43%), and Poland (40.7%), and least often in China (2.4%), the UK (18.8%), and Canada (20.8%).

“In order to improve global vaccination rates, some countries may at present require people to present proof of vaccination to attend work, school, or indoor activities and events,” said CUNY SPH Senior Scholar Jeffrey Lazarus. “Our results found strong support among participants for requirements targeting international travellers, while support was weakest among participants for requirements for schoolchildren.”

Those who were vaccine-hesitant were also less likely to express support for vaccine mandates. “Importantly, however, recommendations by a doctor, or to a lesser extent by an employer, might have an impact on a respondent’s views on vaccination in some countries,” said CUNY SPH Dean Ayman El-Mohandes.

Although some countries are currently disengaging from evidence-based COVID control measures, the disease has by no means been controlled or ended as a public health threat. The authors note that for ongoing COVID vaccination campaigns to succeed in improving coverage going forward, substantial challenges remain. These include targeting those reporting lower vaccine confidence with evidence-based information campaigns and greatly expanding vaccine access in low- and middle-income countries.

The Role of Social Networks

The researchers also held a meeting to explore vaccine messaging. According to data presented from a European survey carried out by the Vaccine Confidence Project, the population group most exposed to social networks, ie people under 24, with secondary or university studies and living in urban areas, are the most reluctant to be vaccinated. Additionally, messages that call for vaccination as a “moral obligation” are strongly rejected compared to those that call for “protection,” which are more commonly well received.

As with previous studies, humour was shown to be one of the most effective ways to convey anti-vaccine messages. Therefore, participants in the meeting agreed on the need to disseminate the benefits of vaccines using this same tool, but without making fun of those who have mistaken beliefs about vaccines. In the face of misinformation, it is important to improve information on vaccination using simple language and channels that reach the population, such as social networks, the participants concluded.

Source: CUNY Graduate School of Public Health and Health Policy

Closure Threat for SA’s COVID Vaccine Plant as Orders Dry up

Female scientist in laboratory
Photo by Gustavo Fring on Pexels

South Africa’s COVID vaccine production plant, the first of its kind in Africa is at risk of closure after failing to secure a single according to a report from Reuters. President Cyril Ramaphosa is reported to be in talks with three other African nations in effort to save the venture.

The World Health Organization had called the licensing deal between Johnson & Johnson and Aspen Pharmacare to manufacture the Aspenovax COVID vaccine, a “transformative moment” in the pursuit of equitable access to vaccines. The vaccine is the J&J adenovirus vector vaccine sold under the Aspen brand.

However, after initial vaccine delivery shortfalls, the African continent is now well stocked with vaccines, while the poor infrastructure hampers vaccine distribution.

“There’ve been no orders received for Aspenovax,” Reuters reported, citing a phone conversation with Aspen senior director Stavros Nicolaou.

“If we don’t get orders, we would have to repurpose these lines back into other things that we were previously doing,” he told CapeTalk.

There are several other such vaccine plants in various stages, as the African Union aims at 60% of locally produced vaccines for continent locally by 2040, up from the current 1%.

“If Aspen doesn’t get production, what chance is there for any of the other initiatives?” Nicolaou remarked.

Regarding possible options, he said: “We are exploring various options. It is our medium-to-long-term objective to look at providing a sterile [processing] platform and solutions for the continent but the short-term needs to be sorted out.”

Moderna announced an agreement with Kenya to set up its first mRNA manufacturing facility in Africa with the aim of producing up to 500 million doses a year.

Source: Seeking Alpha

Rare COVID Vaccine Blood Clots May Result from Genetics

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Scientists have discovered that the rare blood clot side-effect associated with some COVID vaccines could be the result of a specific gene variant, which could make a genetic screening test possible.

Vaccine-induced thrombotic thrombocytopenia (VITT), a rare disorder causing thrombosis and thrombocytopenia (low blood platelet counts), was linked to AstraZeneca’s COVID vaccine in early 2021, leading some countries to pause or restrict its use. It is also associated with the Johnson & Johnson vaccine, which also uses a viral vector.

Now, a new study may help to explain what’s causing the rare side effect. The study by Flinders University and SA Pathology is now available on the medRxiv preprint server and is awaiting peer review.

Examining five unrelated individuals who all had the clotting complication after vaccination, the researchers found that all of the patients had unusually structured antibodies against a protein called platelet factor 4 (PF4), which is involved in blood clotting.

In addition, all five shared a specific version of a gene responsible for producing these antibodies.

“We knew previously that PF4 was directly involved in the clotting disorder, and we knew that aberrant antibodies against PF4 are responsible, but what we don’t know is how and why some people develop them,” explained lead author Dr Jing Jing Wang.

The antibodies were all found to be derived from the same amino acid sequence. The researchers then found that all of the patients carried a specific variant of one gene, called IGLV3-21*02, most commonly occurring in people of European descent.

“The other specific amino acid sequences of these antibodies from each patient were derived from separate basic sequences but had all evolved to carry very similar properties, making them very potent attackers of the PF4 protein,” explained research team leader Professor Tom Gordon.

“Together, this suggests that it is the combination of a variant in a gene and the evolution of this antibody towards targeting the PF4 protein in a destructive manner, which is leading to this harmful side-effect.”

Though why the antibody is found in such a tiny number of vaccine recipients remains unknown, the identification of the gene could enable a genetic screening tool to identify patients who are at risk of this severe complication.

“It also provides a unique opportunity for targeted, specific therapy development aimed at neutralising this highly damaging but very specific antibody,” said Dr Wang.

Source: Flinders University

Three Doses are Needed for Same Protection against Omicron

Syringe injection into the upper arm
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According to a large study published in The BMJ, mRNA vaccines are highly effective in preventing COVID hospital admissions related to the alpha, delta, and omicron variants. However, three doses are needed to achieve similar protection against omicron that two doses provide against delta and alpha.

The results also show that, although severity of disease among patients admitted to hospital is lower with the omicron versus delta variant, patients with omicron are still at risk of critical illness and death.

In order to guide vaccination policies and development of new vaccines, it is essential to understand COVID variants and vaccine efficacy.

Early studies suggested reduced vaccine effectiveness against infection and hospital admissions for omicron compared with earlier variants, but little is known about the effectiveness of vaccines to prevent the most severe manifestations of COVID, including respiratory failure and death, for patients with infection due to the omicron variant.

To address this, the researchers assessed COVID severity in the alpha, delta, and omicron variants among hospitalised adults and compared the effectiveness of two and three doses of mRNA vaccines (Pfizer-BioNTech and Moderna) in preventing hospital admissions related to each variant.

Their findings are based on 11 690 adults admitted to 21 hospitals across the United States between March 2021 and January 2022: 5728 cases with COVID and 5962 controls without COVID.

Patients were classified into alpha, delta or omicron based on viral gene sequencing or by the predominant circulating variant at the time of hospital admission.

Vaccine effectiveness was then calculated for each variant and variants’ disease severity was compared with the World Health Organization’s clinical progression scale.

Effectiveness of two doses of an mRNA vaccine to prevent COVID hospital admission was found to be lower for the omicron variant than alpha and delta variants (65%, 85%, and 85%, respectively), whereas three doses were found to achieve 86% effectiveness against the omicron variant, similar to two doses against the alpha and delta variants.

Among unvaccinated adults hospitalised with COVID, the delta variant was associated with the most severe disease, followed by the alpha variant and then the omicron variant.

The omicron variant was, however, associated with substantial critical illness and death, with 15% of patients admitted to hospital with the omicron variant (vaccinated and unvaccinated) progressing to invasive mechanical ventilation, and 7% dying in hospital.

Nevertheless, vaccinated patients hospitalised with COVID had significantly less sever disease than unvaccinated patients across all variants.

As an observational study, cause cannot be established, and some variant misclassification may have occurred. Changes in clinical management during the periods when the alpha, delta, and omicron variants predominated were not accounted for. These could have affected outcomes, the researchers acknowledged.

Nevertheless, this was a large study with rigorous evaluation of vaccination status and of outcomes beyond hospital admission, suggesting that the results are robust.

As such, they say that mRNA vaccines “were associated with strong protection against hospital admissions with COVID due to the alpha, delta, and omicron variants” and that vaccination against COVID including a third dose of an mRNA vaccine, “is critical for protecting populations against COVID-associated morbidity and mortality.”

They concluded: “As the COVID pandemic continues to evolve, routine monitoring of vaccine effectiveness, especially against severe disease, and surveillance programmes to identify viral variants will be essential to inform decisions about booster vaccine policies and vaccine strain updates.”

Source: EurekAlert!

South African Biotech Company Replicates Moderna Vaccine

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Afrigen Biologics and Vaccines, a South African biotechnology company, has nearly created a copy of Moderna’s COVID mRNA vaccine, without Moderna’s involvement, Nature reports.

The Cape Town-based company has so far made only microlitres of the vaccine, based on Moderna’s publicly available development data. This nevertheless is a success for a major initiative launched by the World Health Organization (WHO): a technology transfer hub meant to build vaccine manufacturing capacity in low- and middle-income countries.

During the COVID pandemic, the developers of mRNA vaccines, Moderna and Pfizer/BioNTech have sent more than 70% of their doses to wealthy nations. Meanwhile, millions of vaccine orders for southern hemisphere countries have been delayed. “Moderna and Pfizer-BioNTech’s vaccines are mainly still going to just the richest countries,” says Martin Friede, the WHO official coordinating the hub. “Our objective is to empower other countries to make their own.”

Much work needs to be done before Afrigen’s mRNA vaccine mimic can be distributed. But the WHO hopes that the process of creating it will lay the foundation for a more globally distributed mRNA vaccine industry in the future.

Gerhardt Boukes, chief scientist at Afrigen is proud to have helped complete this first step of the plan. Afrigen and its collaborators completed the process, beginning with mRNA encoding a modified portion of the SARS-CoV-2 coronavirus, and finishing by encapsulating it in a lipid nanoparticle that delivers the vaccine to cells. “We didn’t have help from the major COVID vaccine producers,” he says, “so we did it ourselves to show the world that it can be done, and be done here, on the African continent.”

When the mRNA hub was launched by the WHO in June 2021, Moderna, Pfizer and BioNTech did not respond to requests to help make their vaccines, so the WHO proceeded without their help. The Moderna vaccine was chosen to copy because there is more freely available data on it, and it has not vowed to enforce its patents.

The project started in late September, with a Wits University team spearheading the first step: making a DNA molecule that would serve as a template to synthesise the mRNA needed in the vaccine. While Moderna controversially patented this sequence, Stanford University researchers had deposited it into the online database Virological.org in March last year.

Patrick Arbuthnot, director of gene therapy research at Wits says, “We were not intimidated, because mRNA synthesis is a fairly generic procedure.” Despite delays in the shipment of raw materials, the team completed this process in ten weeks and sent vials of mRNA to Afrigen in early December.

Around this time, scientists worldwide emailed offers of assistance. Some were researchers at the US National Institutes of Health who had conducted foundational work on mRNA vaccines. Petro Terblanche, Afrigen’s managing director, said that it was “extraordinary”. “I think a lot of scientists were disillusioned with what had happened with vaccine distribution, and they wanted to help get the world out of this dilemma.”

On 5 January, Afrigen’s researchers accomplished another tricky part of the process: They encapsulated the mRNA in a fatty nanoparticle made of a mixture of lipids. Boukes says they haven’t yet used Moderna’s specific lipid mixture, but rather another one that was immediately available from the manufacturer of the machine that the laboratory uses to create lipid nanoparticles. They plan to use Moderna’s lipid mixture in the coming days, as soon as one last analytical instrument arrives. After that, the team will analyse the formulation to ensure that it is truly a near copy of Moderna’s vaccine.

Once a reliable copy is made, the next step is increasing production. Jason McLellan, a structural biologist at the University of Texas at Austin whose work was foundational to the development of several COVID vaccines, says he is not surprised that SA scientists seem to have copied Moderna’s vaccine, but he adds that scaling up production of that original shot required a lot of additional innovation by manufacturers.

For the next phase of the project, several southern hemisphere companies will learn from Afrigen and attempt to create batches of vaccines themselves, in preparation for animal testing. By end November, the WHO expects a Moderna clone to be ready for phase I trials in humans.

What happens beyond that is unclear. Moderna might choose to license its patent (lab research is usually not subject to patent rules), or alternatives may become available, such as next-generation mRNA vaccines that do not require ultracold storage.

Source: Nature

SA Healthcare Bolstered With Vaccine Lab Investment and Loans

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Last week, South African healthcare received a double shot in the arm with the opening of a local vaccine manufacturing facility and the approval of a World Bank loan to bolster social safety nets and health systems.

On Wednesday, President Cyril Ramaphosa and health technology billionaire Dr Patrick Soon-Shiong officially opened a new vaccine manufacturing facility in Brackenfell, Western Cape.

The South African-born entrepreneur has been strongly supporting local healthcare, with R3 billion invested to help SA share vaccine technology with the rest of Africa. His company, ImmunityBio, is developing a T-cell based universal COVID vaccine, currently in Phase III trials in SA. The same adenovirus vector technology it uses is also being tested in cancer vaccines.

“It has been a dream of mine, since I left the country as a young physician, to bring state-of-the-art, 21st century medical care to SA and to enable the country to serve as a scientific hub for the continent,” Dr Shoon-Siong had previously said. The technology transfer will help “establish much-needed capacity and self-sufficiency.”

The hub will transfer technology, know-how and materials for DNA, RNA, adjuvant vaccine platforms and cell therapies to SA.

“There is no reason we couldn’t make 500 million doses a year,” said Dr Soon-Shiong, who is also a Wits alumnus. “Subject to the raw material being available.”

He said he wants to tap the country’s expertise on prevalent diseases such as HIV and cervical cancer. “There are fantastic scientists with deep knowledge about these diseases,” he said. “More so than in America because they see these patients every day.”

President Ramaphosa and Dr Soon-Shiong also launched the Coalition to Accelerate Africa’s Access to Advanced Healthcare, which aims to drive the development of innovative therapeutics and ensure the continent is prepared for future pandemics.

The coalition aims to manufacture a billion doses of the COVID vaccine by 2025 and to develop treatments for conditions including cancer, COVID, tuberculosis and HIV.

South Africa also received approval from the World Bank for a US$750 million COVID relief loan aimed at reducing the worst of the pandemic’s impact on the poor.

“The World Bank budget support is coming at a critical time for us and will contribute towards addressing the financing gap stemming from additional spending in response to the COVID crisis,” said Dondo Mogajane, Director General of the National Treasury. “It will assist in addressing the immediate challenge of financing critical health and social safety net programs whilst also continuing to develop our economic reform agenda to build back better.”

Meanwhile, Health Minister Dr Joe Phaahla warned that South Africa will likely enter a fifth wave when cold temperatures in May, though what COVID variants may drive it remain to be seen.

J&J Booster Shot Reduces Omicron Hospitalisation by 85%

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Administering a booster shot of Johnson & Johnson’s COVID vaccine was found to be 85% effective in preventing serious illness in Omicron-dominated areas, preliminary results from a South African trial study show.

The South African Medical Research Council performed the study on health workers from 15 November to 20 December, but has not yet been peer-reviewed. It found the booster was effective in largely protecting staff as Omicron came to dominate the country.

“The increase in CD8+ T-cells generated by the Johnson & Johnson vaccine may be key to explaining the high levels of effectiveness against severe COVID disease and hospitalisation in the Sisonke 2 study, as the Omicron variant has been shown to escape neutralising antibodies,” Johnson & Johnson reported in a statement. That data showed that the booster jab “provides 85 percent effectiveness against hospitalisation in areas where Omicron is dominant/”

“This adds to our growing body of evidence which shows that the effectiveness of the Johnson & Johnson Covid vaccine remains strong and stable over time, including against circulating variants such as Omicron and Delta,” it continued.

Around half a million South African health staff have received Johnson jabs as part of clinical trials. South Africa has recorded more than 3.5 million cases and 94 000 deaths since the start of the pandemic.

An earlier South African study in December found the Pfizer/BioNTech vaccine to be less effective overall against Omicron, but still reduced hospital admissions by up to 70%.

Source: MedicalXpress

Moderna Narrowly Beats Pfizer in Effectiveness

Image of a syringe for vaccination
Photo by Mika Baumeister on Unsplash

In the first head-to-head comparison of the effectiveness of the Pfizer-BioNTech and Moderna COVID vaccines, researchers examined the electronic health records of veterans who had received each vaccine and found Moderna to be slightly more effective.

The Moderna vaccine’s increased level of protection included a 21% lower risk of documented infection and 41% lower risk of hospitalisation, according to the research team, whose findings were published in the New England Journal of Medicine.

“Both vaccines are incredibly effective, with only rare breakthrough cases,” said Dr J.P. Casas, a member of the research team. “But regardless of the predominant strain – Alpha earlier and then Delta later – Moderna was shown to be slightly more effective.”

Researchers designed their comparative effectiveness study to address the previously unanswered question of which of the two mRNA vaccines is more effective. Effectiveness outcomes were: documented COVID, symptomatic disease, hospitalisation, ICU admission, and death. The investigators drew on the database of US veterans who received one of the two COVID vaccines between early January 2021 and mid-May 2021.

As initially designed, the research focused on the Alpha variant that predominated at the time. The study matched 219 842 recipients of the Pfizer vaccine to the same number of recipients of the Moderna vaccine. The two groups were matched based on a variety of clinical and demographic factors that could affect outcomes.

Over the study’s 24-week follow-up period, the estimated risk of documented infection was 4.52 events per 1000 people in the Moderna vaccine group and 5.75 per 1000 in the Pfizer group, an excess of 1.23 cases per 1000. The investigators also observed smaller excesses of symptomatic COVID (0.44 events), hospitalisation (0.55 events), ICU admission (0.10 events), and death (0.02 events) per 1000 people in the Pfizer group relative to the Moderna group.

This pattern of a lower risk for Moderna held up when Delta was the main strain. In this comparison, excess risk of documented infection over 12 weeks was 6.54 events per 1000 people for the Pfizer vaccine, compared to Moderna. Given the shorter time frame available for this supplementary research, infection was the only outcome researchers analyzed. Also, the estimates were considered less precise because a smaller number of individuals were eligible for this analysis.

Randomised trials comparing the mRNA vaccines against placebos had previously shown both vaccines to be very effective against symptomatic COVID infection (95% effectiveness for Pfizer-BioNTech, 94% for Moderna), borne out by real-world vaccine use.

“Given the high effectiveness of both the Moderna and Pfizer vaccines, confirmed by our study, either one is recommended to any individual offered a choice between the two,” said first author Dr Barbra A. Dickerman. “However, while the estimated differences in effectiveness were small on an absolute scale, they may be meaningful when considering the large population scale at which these vaccines are deployed. This information may be helpful for larger decision-making bodies.”

The massive Veteran Association records system supported a very large sample size. This, in turn, allowed the study to identify even small differences in effectiveness between the Pfizer and Moderna vaccines. The researchers used a methodology known as causal inference to mirror a gold standard randomised trial as closely as possible. Causal inference is a type of data analysis that helps researchers draw firm conclusions about cause and effect.

Using the VA database, vaccine recipients were closely matched on age, sex, race, geographic location, and other attributes that could affect COVID-related outcomes.

“After this careful matching, we found that the two vaccine groups were extremely similar in terms of variables with respect to an extensive set of demographic, geographic, and health-related attributes,” Dr Dickerman said. “This allowed our observational analysis to produce exceptionally credible results during a global emergency, when answers are needed fast and randomised trials can be impractical.”

As the global pandemic continues to unfold, the research team is working on answers relating to the comparative safety, versus effectiveness, of the Pfizer and Moderna vaccines. Dr Dickerman characterises comparative safety as an “additional piece of the puzzle to support vaccine decision-making.”

Even beyond this analysis, further evaluation of the vaccines’ comparative effectiveness and safety is needed, the authors concluded. Meanwhile, given the evidence at hand, the authors concluded about the Pfizer and Moderna vaccines considered in their study, “Given the high effectiveness and safety profile of both mRNA vaccines, either one is strongly recommended.”

Source: EurekAlert!

Six Different Booster Vaccines Found to be Safe and Effective

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The first randomised trial of COVID boosters, published in The Lancet, has shown that six are safe and provoke strong immune responses. Participants have previously received a two-dose course of ChAdOx1-nCov19 (Oxford–AstraZeneca [ChAd]) or BNT162b2 (Pfizer-BioNTech [BNT]). The announcement comes just as the Omicron variant is beginning to spread around the world.

ChAd has now been deployed in more than 180 countries and BNT in more than 145 countries. Several studies show that two doses of ChAd and BNT confer 79% and 90% protection, respectively, against hospitalisation and death after six months. However, protection against COVID infection wanes in time, which has led to the consideration of boosters. However, there are currently little data on the comparative safety of COVID vaccines, and the immune responses they stimulate, when given as a third dose.

The COV-BOOST study looked at safety, immune response (immunogenicity) and side-effects (reactogenicity) of seven vaccines when used as a third booster jab. The vaccines studied were ChAd, BNT, NVX-CoV2373 (Novavax [NVX]), Ad26.COV2.S (Janssen [Ad26]), Moderna [mRNA1273], VLA2001 (Valneva [VLA]), and CVnCov (Curevac [CVn]).

“The side effect data show all seven vaccines are safe to use as third doses, with acceptable levels of inflammatory side effects like injection site pain, muscle soreness, fatigue. Whilst all boosted spike protein immunogenicity after two doses of AstraZeneca, only AstraZeneca, Pfizer-BioNTech, Moderna, Novavax, Janssen and Curevac did so after two doses of Pfizer-BioNTech”, commented Professor Saul Faust, trial lead.

“It’s really encouraging that a wide range of vaccines, using different technologies, show benefits as a third dose to either AstraZeneca or Pfizer-BioNTech. That gives confidence and flexibility in developing booster programmes here in the UK and globally, with other factors like supply chain and logistics also in play”, added Prof Faust.

“It’s important to note that these results relate only to these vaccines as boosters to the two primary vaccinations, and to the immune response they drive at 28 days. Further work will generate data at three months and one year after people have received their boosters, which will provide insights into their impact on long-term protection and immunological memory. We are also studying two of the vaccines in people who had a later third dose after 7-8 months although results will not be available until the new year.”

A randomised, phase 2 trial of seven booster vaccines was conducted, with the third doses given 10-12 weeks after initial two-dose courses of ChAd or BNT. The trial involved 2878 healthy participants between June 1st and June 30th 2021. Participants had received their first doses of ChAd or BNT in December 2020, January or February 2021, and second doses at least 70 days before enrolment for ChAd and at least 84 days for BNT. About half of participants received two doses of ChAd and half two doses of BNT. The control vaccine used was a meningococcal conjugate vaccine (MenACWY).

Participants were aged 30 or older, roughly half of whom were 70 or older. The average age of participants who received ChAd was 53 years in the younger age group and 76 years in the older age group. Average ages for BNT were 51 and 78 years, respectively.

Thirteen experimental and control arms of the trial (seven vaccines plus three at half dose and three control arms) were split into three participant groups. Group A received NVX, half dose NVX, ChAd, or a control. Group B received BNT, VLA, half dose VLA, Ad26 or a control. Group C received Moderna, CVn (development of which was halted in October 2021), half dose BNT, or a control.

Primary outcomes were adverse effects seven days after receiving a booster, and levels of antibodies targeting the SARS-CoV-2 Spike protein after 28 days, compared to controls. Secondary outcomes included the response of T cells to wild type, Alpha, Beta, and Delta variants. 

Increases in anti-spike protein antibody levels after 28 days varied across the vaccines. After two doses of ChAd these ranged from 1.8 times higher to 32.3 times higher according to the booster vaccine used. Following two doses of BNT, the range was 1.3 times higher to 11.5 times higher. Significant T-cell responses were reported in several combinations.

At 28 days, all booster results were similar for participants aged 30-69 years and those aged 70 years or older. Boost ratios should be interpreted with caution, the authors caution, since they relate to immunogenicity rather than protection against disease, and the relationship between antibody levels at day 28 and long-term protection and immunological memory is unknown.

Reactions to all seven vaccines were similar, with fatigue, headache, and injection site pain most often reported. These were more commonly reported by those aged 30-69. 912 of the 2878 participants experienced a total of 1036 adverse events, 24 of which were severe.

Source: EurekAlert!

Mechanism Behind AstraZeneca and J&J Vaccine Blood Clots Found

A cloud of platelet factor 4 proteins interacting with the electrostatic surface of the Oxford vaccine, as seen through the computational microscope.
Credit: Chun Kit Chan, Arizona State University

An international team of scientists believe they may have found a molecular mechanism behind the extremely rare blood clots linked to adenovirus vaccines.

Scientists led by a team from Arizona State University, Cardiff University and others worked with AstraZeneca to investigate vaccine-induced immune thrombotic thrombocytopenia (VITT), also known as thrombosis with thrombocytopenia syndrome (TTS), a life-threatening condition seen in a very small number of people after receiving the Oxford-AstraZeneca or Johnson & Johnson vaccines.

“The mechanism which results in this condition, termed vaccine-induced immune thrombotic thrombocytopenia (VITT), was unknown,” said Abhishek Singharoy, an Arizona State University scientist and corresponding author of the study who teamed up to lead an international effort to tease out the details. 

Together, the team worked to solve the structural biology of the vaccine, and see the molecular details that may be at play, utilising state-of-the cryo-EM technology to analyse the AstraZeneca vaccine in minute detail. They sought to understand whether the ultra-rare side effect could be linked to the viral vector which is used in many vaccines, including those from Oxford/AstraZeneca and Johnson & Johnson.

Their findings suggest it is the viral vector – in this case, an adenovirus used to shuttle the coronavirus’ genetic material into cells – and the way it binds to platelet factor 4 (PF4) once injected that could be the potential mechanism.

In very rare cases, the scientists suggest, the viral vector may enter the bloodstream and bind to PF4, where the immune system then views this complex as foreign. They believe this misplaced immunity could result in the release of antibodies against PF4, which bind to and activate platelets, leading to clustering and blood clotting.

“It’s really critical to fully investigate the vector-host interactions of the vaccine at a mechanistic level,” said Singharoy. “This will assist in understanding both how the vaccine generates immunity, and how it may lead to any rare adverse events, such as VITT.”

Their findings were published in Science Advances.

Adenovirus expert Professor Alan Parker said: “VITT only happens in extremely rare cases because a chain of complex events needs to take place to trigger this ultra-rare side effect. Our data confirms PF4 can bind to adenoviruses, an important step in unravelling the mechanism underlying VITT. Establishing a mechanism could help to prevent and treat this disorder.”

“We hope our findings can be used to better understand the rare side effects of these new vaccines – and potentially to design new and improved vaccines to turn the tide on this global pandemic.”

The AstraZeneca and Johnson & Johnson vaccines both use an adenovirus to carry SARS-CoV-2 Spike proteins to trigger an immune response.

Since VITT was seen in both vaccines, scientists wondered whether the viral vector was involved. Additionally, neither the Moderna nor Pfizer vaccines, both mRNA vaccines, showed this effect.

Using cryo-EM technology to flash-freeze preparations of ChAdOx1, the adenovirus used in the AstraZeneca vaccine, they produce microscopic images of the vaccine components.

They were then able to view the viral capsid structure and other critical proteins that allow entry of the virus into the cell.

In particular, the team outlined the details for the structure and receptor of ChAdOx1, which is adapted from chimpanzee adenovirus Y25 – and how it interacts with PF4. They believe it is this specific interaction – and how it is then presented to the immune system – that could cuase the immune system to see it as foreign and release antibodies against this self-protein.

The research team also used computational models to show that one of the ways the two molecules tightly bind is via electrostatic interactions. The group showed that ChAdOx1 is mostly electronegative, attracting other positively charged molecules to its surface.

First author Dr Alexander Baker said: “We found that ChAdOx1 has a strong negative charge. This means the viral vector can act like a magnet and attract proteins with the opposite, positive charge, like PF4.” Baker is a member of ASU’s Biodesign Center for Applied Structural Discovery and an Honorary Research Fellow at Cardiff University School of Medicine.

“We then found that PF4 is just the right size and shape that when it gets close to ChAdOx1 it could bind in between the negatively charged parts of ChAdOx1’s surface, called hexons.”

The research team are hopeful that armed with a better understanding of what may be causing rare VITT they can provide further insights into how vaccines and other therapies, which rely on the same technology, might be altered in the development of the next generation vaccines and therapies.

“With a better understanding of the mechanism by which PF4 and adenoviruses interact there is an opportunity to engineer the shell of the vaccine, the capsid, to prevent this interaction with PF4. Modifying ChAdOx1 to reduce the negative charge may reduce the chance of causing thrombosis with thrombocytopenia syndrome,” said Baker.

The team likened it to the ‘two birds, one stone’ effect. The key contacts of individual amino acids that are essential to the capsid protein’s proteins interaction with PF4 can removed or substituted.

“The modification of the ChAdOx1 hexons to reduce their electronegativity may solve two problems simultaneously: reduce the propensity to cause VITT to even lower levels, and reduce the levels of pre-existing immunity, thus helping to maximize the opportunity to induce robust immune responses, said Singharoy.”

Source: EurekAlert!