Oxford-AstraZeneca vaccination followed by mRNA vaccine boost

 

TO THE EDITOR:

Because of concerns about thrombotic events after vaccination with ChAdOx1 nCoV-19 (Oxford–AstraZeneca),1 several European countries have recommended heterologous messenger RNA (mRNA) boost strategies for persons younger than 60 or 65 years of age who have received one dose of ChAdOx1 nCoV-19.2 To date, data on the safety and immunogenicity of these regimens are limited.

Through an ongoing clinical study of the longitudinal immunogenicity of coronavirus disease 2019 (Covid-19) vaccines (EudraCT number, 2021-000683-30. opens in new tab; the protocol is available with the full text of this letter at NEJM.org), we were able to assess 88 health care workers who had received one dose of ChAdOx1 nCoV-19 vaccine 9 to 12 weeks earlier. Among these participants, 37 chose a homologous boost with ChAdOx1 nCoV-19 and 51 chose a heterologous boost with mRNA-1273 (Moderna). The median age of the participants was 46 years (range, 28 to 62) and 40 years (range, 23 to 59), respectively. Blood specimens were obtained at the time of boost, 7 to 10 days after the boost, and 30 days after the boost. Levels of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (S)–specific and receptor-binding domain (RBD)–specific IgG were assessed with the use of an enzyme-linked immunosorbent assay and expressed as the area under the curve. Serum neutralization of the original SARS-CoV-2 isolate from Sweden (SARS-CoV-2/01/human/2020/SWE; GenBank accession number, MT093571.1. opens in new tab) was measured in an immunofluorescence assay, with results expressed as the reciprocal of the 50% inhibitory dilution (ID50); serum neutralization of the original SARS-CoV-2 isolate from Sweden and the B.1.351 (or beta) variant was also measured in a cytopathic effect assay. Information on reactogenicity before and after administration of the booster injection was reported by the study participants. Demographic characteristics of the participants and full details of the methods are provided in the Supplementary Appendix, available at NEJM.org.

On the day of the boost, the two groups had similar levels of SARS-CoV-2 S-specific and RBD-specific IgG and neutralizing antibodies. Levels of S-specific and RBD-specific IgG at 7 to 10 days after a ChAdOx1 nCoV-19 boost were 5 times as high as on the day of the boost (P<0.001); at 7 to 10 days after an mRNA-1273 boost, levels of S-specific IgG were 115 times as high and levels of RBD-specific IgG were 125 times as high as on the day of the boost (P<0.001) (Fig. S1 in the Supplementary Appendix). After 30 days, levels of S-specific IgG remained similar to those at the 7-to-10-day time point in both groups.

The potent induction of SARS-CoV-2 S-specific antibodies after a heterologous boost with mRNA-1273 was reflected by an increase in the in vitro reciprocal serum neutralization titer, with a reciprocal ID50 at 7 to 10 days after the boost that was 20 times as high as that on the day of the boost (P<0.001) (Figure 1A). In contrast, a homologous ChAdOx1 nCoV-19 boost led to a near doubling of the reciprocal ID50 within 7 to 10 days (P=0.09). At 1 month after the boost, an additional increase in neutralizing antibodies (to levels 1.6 to 1.7 times as high as the levels at 7 to 10 days) occurred in both groups, but the increase was not significant. We verified our results for neutralization of the original SARS-CoV-2 isolate from Sweden in another laboratory (Figure 1B). In addition, we found that an mRNA-1273 boost had induced antibodies that could neutralize the B.1.351 variant of SARS-CoV-2 (Figure 1B); however, a ChAdOx1 nCoV-19 boost did not induce potent neutralizing antibodies against this variant, a finding consistent with findings from a previous study.3

In this relatively small cohort, the mRNA-1273 boost led to more frequent reports of fever, headache, chills, and muscle aches than the ChAdOx1 nCoV-19 boost. However, we found no significant difference between the groups when the events were graded according to intensity level (Fig. S2). The reported adverse events are in line with what has been published previously for homologous ChAdOx1 nCoV-19 or mRNA-127 vaccination regimens.4,5

We conclude that the mRNA-1273 vaccine can efficiently stimulate the SARS-CoV-2–specific B-cell memory that has been generated by a prime dose of ChAdOx1 nCoV-19 vaccine 9 to 12 weeks earlier and that it may provide better protection against the B.1.351 variant than a ChAdOx1 nCoV-19 boost. These data also suggest that mRNA vaccines (here in the form of mRNA-1273) may be useful for vaccination strategies in which a third dose is to be administered to persons who have previously received two doses of ChAdOx1 nCoV-19.

Johan Normark, M.D., Ph.D.
Linnea Vikström, B.Sc.
Yong-Dae Gwon, Ph.D.
Ida-Lisa Persson, B.Sc.
Alicia Edin, M.D., Ph.D.
Tove Björsell, M.Sc.
Andy Dernstedt, M.Sc.
Umeå University, Umeå, Sweden

Wanda Christ, M.Sc.
Karolinska Institutet, Stockholm, Sweden

Staffan Tevell, M.D., Ph.D.
Region Värmland, Karlstad, Sweden

Magnus Evander, Ph.D.
Umeå University, Umeå, Sweden

Jonas Klingström, Ph.D.
Karolinska Institutet, Stockholm, Sweden

Clas Ahlm, M.D., Ph.D.
Mattias Forsell, Ph.D.
Umeå University, Umeå, Sweden
mattias.forsell@umu.se

Supported by grants from Vetenskapsrådet (2020-06235, to Dr. Forsell, and 2020-05782, to Dr. Klingström), SciLife Laboratories (VC-2020-0015, to Dr. Forsell), Region Västerbotten and Umeå University (RV-938855, to Dr. Ahlm), and the Center for Innovative Medicine (CIMED) (20200141, to Dr. Klingström). Dr. Normark is a Wallenberg Center for Molecular Medicine Associated Researcher.

Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

This letter was published on July 14, 2021, at NEJM.org.

https://www.nejm.org/doi/full/10.1056/NEJMc2110716

High dose oral vitamin D therapy impact on inflammatory markers in COVID 19

 

Maheshwar Lakkireddy, 

Srikanth Goud Gadiga, 

R. D. Malathi, 

Madhu Latha Karra, 

I. S. S. V. Prasad Murthy Raju, 

Ragini, 

Sangeetha Chinapaka, 

K. S. S. Sai Baba & 

Manohar Kandakatla 

• DOIhttps://doi.org/10.1038/s41598-021-90189-4

PDF: https://www.nature.com/articles/s41598-021-90189-4.pdf

Abstract

COVID 19 is known to cause immune dysregulation and vitamin D is a known immunomodulator. This study aims to objectively investigate the impact of Pulse D therapy in reducing the inflammatory markers of COVID-19. Consented COVID-19 patients with hypovitaminosis D were evaluated for inflammatory markers (N/L ratio, CRP, LDH, IL6, Ferritin) along with vitamin D on 0th day and 9th/11th day as per their respective BMI category. Subjects were randomised into VD and NVD groups. VD group received Pulse D therapy (targeted daily supplementation of 60,000 IUs of vitamin D for 8 or 10 days depending upon their BMI) in addition to the standard treatment. NVD group received standard treatment alone. Differences in the variables between the two groups were analysed for statistical significance. Eighty seven out of one hundred and thirty subjects have completed the study (VD:44, NVD:43). Vitamin D level has increased from 16 ± 6 ng/ml to 89 ± 32 ng/ml after Pulse D therapy in VD group and highly significant (p < 0.01) reduction of all the measured inflammatory markers was noted. Reduction of markers in NVD group was insignificant (p > 0.05). The difference in the reduction of markers between the groups (NVD vs VD) was highly significant (p < 0.01). Therapeutic improvement in vitamin D to 80–100 ng/ml has significantly reduced the inflammatory markers associated with COVID-19 without any side effects. Hence, adjunctive Pulse D therapy can be added safely to the existing treatment protocols of COVID-19 for improved outcomes.

Funding

Sponsored by Pulse Pharmaceuticals. Funding source has no involvement in study design, collection, analysis, interpretation of data, writing the report or decision to submit the article for publication.

Competing interests

The authors declare no competing interests.

https://www.nature.com/articles/s41598-021-90189-4

Metal-based molecules show promise against build-up of Alzheimer's peptides

 In lab tests, Imperial researchers have created a metal-based molecule that inhibits the build-up of a peptide associated with Alzheimer's disease.

A peptide is a fragment of a protein, and one of the key hallmarks of Alzheimer's disease is the build-up of a specific peptide known as amyloid-β. The team demonstrated that with the aid of ultrasound, their molecule can cross the blood-brain barrier in mice, targeting the part of the brain where the damaging peptide most often accumulates.

Alzheimer's disease is the most common form of dementia, affecting approximately 50 million people worldwide. There is a pressing need to develop drugs that can prevent or reverse the effects of this devastating disease.

Some metal-based molecules have been previously designed to prevent amyloid-β from building up. However, these are often toxic to cells, or are unable to cross the blood-brain barrier (BBB) -- a semi-permeable protective barrier that carefully regulates the passage of substances that enter and exit the brain.

Now, a team from the Departments of Chemistry and Bioengineering at Imperial College London have designed a metal-based molecule that is highly effective at preventing the build-up of amyloid-β in lab-based studies.

They also showed that the molecule is non-toxic to human brain-like cells, and that it can cross the blood-brain barrier in mice with the help of a technique using microbubbles and focused ultrasound. The results are reported in the journal Chemical Science.

First author Tiffany Chan, from the Departments of Chemistry and Bioengineering at Imperial, said: "Very few metal-based molecules have been investigated as potential inhibitors of amyloid-β build-up because of toxicity issues and difficulty crossing the blood brain barrier. The molecule we have designed is able to interfere with amyloid-β and seems non-toxic, and it can be delivered across the blood brain barrier using ultrasound, which means you don't need an invasive procedure."

The molecule is centred around the metal cobalt, surrounded by organic molecules that form a complex, which binds to amyloid-β peptides, preventing them from binding to each other and building up. The molecule also incorporates chemical groups that prevent it from being taken up into human nerve cells, reducing its toxicity.

To demonstrate the molecule could cross the BBB, the team used a technique that involves injecting the molecule alongside microbubbles into the veins of mice. When ultrasound is directed at the brain, the microbubbles rapidly move back and forth, opening the BBB and allowing the molecule to enter the brain in a non-invasive and targeted manner.

The team were able to focus the ultrasound on the hippocampal region of the brain, which is often strongly impacted by the build-up of amyloid-β in the early stages of Alzheimer's disease. They were also able to show how specific the ultrasound targeting can be by delivering the molecule only to the left hippocampus.

The molecule was shown to be well tolerated by the mice, who showed no ill effects after several weeks. Co-author Professor Ramon Vilar, from the Department of Chemistry at Imperial, said: "This study shows the potential that metal-based molecules have in preventing amyloid-β aggregation. The new compound will be studied in more depth to establish whether it can also prevent amyloid-β build-up in mice without having unwanted toxic side effects."

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Story Source:

Materials provided by Imperial College London. Original written by Hayley Dunning. Note: Content may be edited for style and length.

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Journal Reference:

1. Tiffany G. Chan, Carmen L. Ruehl, Sophie V. Morse, Michelle Simon, Viktoria Rakers, Helena Watts, Francesco A. Aprile, James J. Choi, Ramon Vilar. Modulation of amyloid-β aggregation by metal complexes with a dual binding mode and their delivery across the blood–brain barrier using focused ultrasound. Chemical Science, 2021; 12 (27): 9485 DOI: 10.1039/D1SC02273C

https://www.sciencedaily.com/releases/2021/07/210714110549.htm

Human cells harness power of detergents to wipe out bacteria

 Cells, like many of us, fend off germs with cleaning products.

Researchers have discovered that a molecule made throughout much of the body wipes out invading bacteria like a detergent attacking an oily stain.

This killer cleaner, a protein known as APOL3, thwarts infections by dissolving bacterial membranes, Howard Hughes Medical Institute Investigator John MacMicking and his colleagues report in the journal Science on July 15, 2021. His team tested the protein on the food-poisoning bacteria Salmonella and other similar microbes.

The work offers new insight into how human cells defend themselves against infection, a process termed cell-autonomous immunity. While scientists knew that cells could attack bacterial membranes, this study uncovers what appears to be the first example of a protective intracellular protein with detergent-like action.

MacMicking hopes the findings could one day aid efforts to develop new treatments for infections. "This is a case where humans make their own antibiotic in the form a protein that acts like a detergent," says MacMicking, an immunologist at Yale University. "We can learn from that."

Breaching barriers

When it comes to defending the human body, the specialized cells of the immune system act as a crew of cellular bodyguards. But the same alarm signals that mobilize these cells can also activate average citizens. A signal called interferon gamma, for instance, cranks up protein production in non-immune cells that compose our tissues and organs. But scientists know little about how such proteins help cells fight pathogens.

The researchers infected some of these non-immune cells with a strain of Salmonella, which invades cells' watery interiors. Salmonella belongs to a class of bacteria bounded by two membranes. The outer bacterial membrane acts like armor, protecting the inner bacterial membrane from threats like antibiotics.

The team found that the interferon gamma alarm signal could prevent Salmonella from taking over human cells, but the researchers didn't know which proteins came to the rescue. MacMicking's team screened more than 19,000 of the human cells' genes, looking for ones that might encode protective proteins. That work led the researchers to discover APOL3, which receives assistance from a second molecule, GBP1, and probably others. Using high-resolution microscopy and other techniques, the team pieced together the mechanism: GBP1 damages a bacterium's outer membrane, allowing APOL3 through so it can break apart the inner membrane -- the "coup de grace" that kills the bacterium, MacMicking says.

Like a laundry detergent, APOL3 possesses parts attracted to water and parts drawn to grease. Instead of removing dirt from fabric, these components remove chunks of the bacterial inner membrane, which is composed of greasy molecules called lipids.

This process must be highly selective, MacMicking says, since APOL3 needs to avoid attacking membranes of the human cell itself. The team found that APOL3 avoids cholesterol, a major constituent of cell membranes, and instead targets distinctive lipids favored by bacteria.

A new defender

APOL3 appears likely to be in the toolbox of many cells. MacMicking's team showed it defends cells within the blood vessels and gut. Because APOL3 appears in a variety of body tissues, the scientists believe it offers wide protection.

The discovery of this detergent-like molecule within non-immune cells "adds more evidence to the view that any cell in the body can be part of the immune system," says Carl Nathan, who studies host-pathogen interactions at Weill Cornell Medical College, and who was not involved in this research. "It also adds a new example of one of the limited ways living things kill each other," he notes.

Whether perforating, poisoning, or starving a pathogen, the immune system has developed several methods for killing threatening cells. APOL3 joins the group of mechanisms already known to fatally break down membranes, Nathan says.

Researchers are still a long way from being able to apply this discovery to therapies for infections. But deciphering the body's defenses could give humanity new tools against microbes that are increasingly evolving ways to thwart conventional antibiotics. Dialing up cellular detergents and other devices the body uses to kill bacteria, for instance, could help supplement the natural immune response, MacMicking says.

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Story Source:

Materials provided by Howard Hughes Medical Institute. Note: Content may be edited for style and length.

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Journal Reference:

1. Ryan G. Gaudet, Shiwei Zhu, Anushka Halder, Bae-Hoon Kim, Clinton J. Bradfield, Shuai Huang, Dijin Xu, Agnieszka Mamiñska, Thanh Ngoc Nguyen, Michael Lazarou, Erdem Karatekin, Kallol Gupta, John D. MacMicking. A human apolipoprotein L with detergent-like activity kills intracellular pathogens. Science, 2021; 373 (6552): eabf8113 DOI: 10.1126/science.abf8113

https://www.sciencedaily.com/releases/2021/07/210715142350.htm

Summer School Just Started, Scores Of City Classrooms Already Closed Due to COVID

 New York City's expanded summer school aims to help kids prepare for in-person learning this fall. The free program kicked off last week and 200,000 students are participating. But in a sign of challenges ahead, more than 80 classrooms are already in quarantine because of positive COVID-19 cases among teachers or students. 

City protocol says any class with a positive case has to go remote for 10 days. Some parents worry that sticking with this closure rule will mean more disruption this fall, and say the city should consider changing it.  But city health officials said the closures, along with masks, testing, and social distancing, help keep schools safe and are likely to stay in place.

“Our classroom quarantine policy was a key part of our layered approach to preventing the spread of COVID-19 in schools,” city health commissioner Dave Chokshi said on Thursday. He added that he expects “testing as well as isolation and quarantine … will continue to be a key part of our approach going forward.” 

Previously, the city relied on a two-case trigger for school closures. But that came under intense fire from parents last winter and spring, as school after school shuttered for weeks at a time, causing constant disruptions to students’ schedules and leaving parents scrambling for childcare. Multiple scientists criticized the policy, which did not follow Centers for Disease Control guidelines. The mayor changed the school closure threshold in the spring, but the protocol for classroom closures remains. 

According to the education department, classroom closures actually refer to more than physical classrooms. The agency said the term includes any group of students or staff who are close contacts to a confirmed case and are quarantining, including a member of the facilities team. 

The case rate in schools remains extremely low, with 0.12% positivity within the pool of randomly tested students and staff. As of Friday, the citywide seven-day average positivity rate was 1.4%; officials eyeing the threat of the delta variant especially amongst unvaccinated populations.

The education department said routine surveillance testing has identified 12 cases in summer school so far encompassing seven students and five staff members over the past two weeks, and there will be more information on closure policies in the coming weeks. 

But Dr. Elissa Perkins, Director of Emergency Medicine Infectious Disease Management at Boston Medical Center, said classroom closures are unnecessary if other mitigation strategies like masks and social distancing are in place. “I think it's extreme,” she said. “I don't think it's the right decision to close a classroom just because of one case.” 

Perkins said data shows schools have been both “amazingly safe and necessary environments.” She worries classroom closures lead to other, potentially more dangerous challenges by threatening consistency, socialization, and education for kids; and making it more difficult for parents to return to work.

Benjamin Linas, professor of Medicine and Epidemiology at Boston University, called the 10-day classroom closure “over-sensitive” and “too much.” He said when there’s a positive case, there should be an investigation and contact tracing. Quarantines may be necessary for kids who are close together without masks for an extended period of time, per the CDC’s definition of close contacts, but not simply because they’re in the same room. “I think we need to be more precise,” he said. 

However, Dr. Leana Wen, emergency physician and professor at George Washington University, said many parents may prefer to be informed if there is a positive case in a class and choose to quarantine their kids. 

“This is an extremely complicated issue,” she said. “Different parents are going to come to different conclusions about the level of risk they can tolerate. … I do think it’s important to err on the side of caution. Even though children are less likely to be severely affected than adults, they can still become ill, and even if they are only mildly symptomatic they can have long-term consequences.” 

The Centers for Disease Control and Prevention updated its guidance for schools last week, emphasizing an urgency to get students back to schools, and relaxing some recommendations around social distancing and masks. It advised students and staff to remain three-feet apart when possible and said vaccinated individuals should not have to wear masks. It maintained language that students in a classroom should not be considered close contacts who need to quarantine if they were wearing masks and social distancing. City and state officials said they’re still reviewing the guidance.

Speaking on the Brian Lehrer Show Friday, Mayor Bill de Blasio said the number of summer school kids in quarantine is small compared to the number served in the expanded program, which was open to all interested students to help them catch up academically from the disruptions of the pandemic. 

“We’ve got a handful of classrooms that had to quarantine compared to 200,000 kids in Summer Rising,” he said. “It’s still a very rare thing in our public school settings, and we’re two months away from the opening of school so we certainly have time to make adjustments.”

https://gothamist.com/news/summerschool-just-started-and-scores-city-classrooms-are-already-closed-due-covid

Mexico says will soon authorize Moderna's COVID vaccine

 Mexico will soon authorize Moderna Inc's COVID-19 vaccine, Foreign Minister Marcelo Ebrard said on Saturday.

"Good news: soon, very soon, the Moderna vaccine with a technological profile similar to that of Pfizer will be approved in Mexico," Ebrard said on a Twitter post.

https://finance.yahoo.com/news/mexico-says-soon-authorize-modernas-183102288.html

Glaxo, Viiv: long-acting HIV regimen can succeed in range of US health practices, even in COVID

 

• Healthcare teams from a wide variety of US HIV clinics reported that optimal implementation of long-acting cabotegravir and rilpivirine dosed monthly was achieved within 1 - 3 months, and implementation was acceptable, appropriate and feasible
• Majority of patients (74%) in the study reported few barriers to monthly injection appointments even during COVID-19

ViiV Healthcare, the global specialist HIV company majority owned by GlaxoSmithKline plc ('GSK'), with Pfizer Inc. and Shionogi Limited as shareholders, today presented positive findings from the CUSTOMIZE (Cabotegravir plus Rilpivirine long acting in the US To Optimize and Measure Implementation and Experience) trial. The study, which included people living with HIV and healthcare teams and overlapped with the COVID-19 pandemic, demonstrated that Cabenuva (a co-pack with two injectable medicines including ViiV Healthcare's cabotegravir and Janssen's rilpivirine) can be successfully implemented across a range of healthcare settings in the US.[i]The 12-month findings were presented at the International AIDS Society Conference 2021 (IAS 2021) being held virtually 18-21 July.

CUSTOMIZE was initiated in 2019 to identify successful methods of integrating the long-acting regimen of cabotegravir and rilpivirine (dosed monthly) for the treatment of HIV-1 after product availability into clinical practices in the US, in a variety of clinic types.1^,[ii] This study included a variety of clinic types from private practices, university clinics and federally qualified health centres, to integrated health care systems.1Regardless of clinic types, the majority of healthcare staff (96%, n=22/23) either agreed, or completely agreed, that the long-acting regimen was feasible to implement in their clinic, and most (78%, n=18/23) felt that optimal implementation was achieved within 1-3 months, with only minor adjustments to clinic logistics required.1

The people living with HIV who participated in the trial agreed that the long-acting regimen was acceptable and appropriate to implement, with the majority (97%, n=99/102) expressing interest in continuing to receive the long-acting regimen over daily oral therapy after the study ended at Month 12.[iii]In addition to assessing the implementation of cabotegravir and rilpivirine long acting into US healthcare practices, the CUSTOMIZE trial also assessed the safety and efficacy of the regimen. Over the course of the study, findings showed that 100% of participants with available viral load results maintained viral suppression ([iv]Injection site reactions were the most common overall adverse event, reported in 72% (78/109) of participants who received ≥1 injection through Month 12.⁴

^{https://www.marketscreener.com/quote/stock/GLAXOSMITHKLINE-PLC-9590199/news/GlaxoSmithKline-ViiV-Healthcare-study-shows-new-long-acting-HIV-regimen-Cabenuva-cabotegravir-ril-35882713/}