SARS-CoV-2 oral vaccine candidate found to induce neutralizing mucosal IgA

 A new study posted to the medRxiv* preprint server reported the outcomes of a clinical trial evaluating an oral vaccine candidate against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 

The present study examined an oral vaccine platform that promotes adaptive immune responses at mucosal surfaces, key entry points for respiratory infections such as SARS-CoV-2.

Mucosal immunity is the largest component of the immune system protecting the mucosa – the primary site of infection. Mucosal immunoglobulin (Ig)A production exceeds that of every other immunoglobulin isotype. Moreover, mucosal IgA demonstrates increased neutralization activity against SARS-CoV-2 in vitro, along with greater cross-reactivity with other viral types. Mucosal membranes act as barriers against most foreign substances; the majority of pathogens are destroyed and eliminated by the immune cells of mucosal membranes that surround the eye conjunctiva, inner ear, aerodigestive, urogenital, and exocrine gland ducts. 

The development of mucosal vaccines for various microbial diseases, such as SARS-CoV-2, is a major field of research. This is because SARS-CoV-2 infection begins in the upper respiratory tract and largely affects the respiratory mucosa. Consequently, if a mucosal vaccination against SARS-CoV-2 is developed, it would offer the required level of protection at the infection site, thereby preventing infections and inhibiting virus replication in the upper respiratory tract.

Current vaccines are ineffective since they do not provide a broad spectrum of immunity and cannot combat infections caused by SARS-CoV-2 mutant strains such as Omicron. There exists a widespread agreement regarding the current necessity of novel vaccine techniques. 

In this regard, this study examined a shelf-stable, oral tablet vaccination developed by Vaxart that contains both the spike (S) and nucleocapsid (N) proteins. Vaxart's vaccine platform comprises an Adenovirus type 5 (Ad5) backbone and a toll-like receptor-3 (TLR3) agonist adjuvant. These vaccines have been tested in more than 650 patients and were well tolerated and were found to generate magnanimous humoral and cellular immune responses to the expressed antigens in the past. 

A phase 1 clinical trial was conducted in a single center, open-label, dose-ranging fashion to determine the tolerance and efficacy of two dose levels of the oral COVID-19 vaccine candidates, designated as VXA-CoV2-1.

The study enrolled a greater proportion of males (65.7%) than females (34.3%). Participants in this trial received the following prophylaxis – Cohort 1 received a low dose of the oral vaccine with a 29th-day booster; Cohort 2 received a single low dosage; and Cohort 3 was administered a single high dose.

In the clinical studies, 35 adult participants who met the inclusion/exclusion criteria got either a single low (1x1010 IU) or high (5x1010 IU) dose, whereas five participants received two low doses. Researchers examined nasal, salivary, and serum samples for the presence of IgA, IgG, and substitute neutralizing antibodies. Convalescent individuals at the post-infection phase – one and eight months after a confirmatory test result, were enlisted to provide nose, saliva, and serum samples for analysis. 

Safety was the primary goal of this trial. The immunogenicity secondary endpoint was evaluated during the active phase (Day-29 or Day-57) largely by quantifying IgA and IgG in the nose, serum, and saliva samples. The long-term durability of available volunteers was evaluated.

Findings

Clinical trials have demonstrated that VXA-COV2-1, the candidate oral tablet vaccine against SARS-CoV-2, was well tolerated and immunogenic. The majority of the participants had elevated mucosal IgA responses specific to SARS-CoV-2 S and N proteins and receptor-binding domain (RBD), but minimal serum responses.

In most responders, a single injection of VXA-CoV2-1 produced cross-reactive IgA lasting beyond 180 days. IgA specific for SARS-CoV-2 increased in both, nasal and salivary secretions. Besides, nasal IgA was found to be secretory IgA, which has been demonstrated to neutralize SARS-CoV-2 more effectively in vitro, than monomeric IgA. 

Convalescents and VXA-CoV2-1 produced comparable amounts of IgA in the nose and saliva. Additionally, researchers noted that vaccine-immunized patients have enhanced mucosal neutralizing antibody responses, implying that vaccination may enhance the quality of antibody responses on mucosal surfaces. Mucosal IgA produced by VXA-CoV2-1 was cross-reactive to the Omicron and the Delta variants of SARS-CoV-2. At the same time, the saliva and nasal samples collected 29 days after immunization were also cross-reactive to other human variants of concern like the Alpha and Beta mutants. 

There was cross-reactivity between the IgA produced by vaccination and S proteins across the coronaviridae family rather than the preferential specificity to the antigen that the vaccine recognized. The surrogate neutralizing activity of the vaccine persisted beyond 180 days in most responders, with the levels still exceeding the pre-vaccination levels.

Major shortcomings of this study were that the trial was small and included few subjects and that the vaccine was evaluated before messenger ribonucleic acid (mRNA) vaccines were commercially accessible.

Conclusion 

VXA-CoV-2 was well received and induced cross-reactive neutralizing mucosal IgA responses in most respondents, lasting up to 180 days.

VXA-CoV-2 is the first oral vaccine against SARS-CoV-2 which has demonstrated both safety and immunity in humans. Future studies will examine variations in dosage, antigen recognition, and efficacy in larger human trials.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:

• Johnson, S., Martinez, C., Jegede, C., et al. (2022). SARS-CoV-2 oral tablet vaccination induces neutralizing mucosal IgA in a phase 1 open label trial. medRxiv. Doi: 10.1101/2022.07.16.22277601 https://www.medrxiv.org/content/10.1101/2022.07.16.22277601v1

https://www.news-medical.net/news/20220725/SARS-CoV-2-oral-vaccine-candidate-found-to-induce-neutralizing-mucosal-IgA.aspx

Chinese Stocks Underperform S&P 500 Most Since 2016

 By George Lei, Bloomberg Markets Live commentator and analyst

Three things we learned last week:

1. Optimism toward China’s growth recovery got a reality check last week, when the Politburo meeting made two things clear: the Covid Zero policy is here to stay and large stimulus is unlikely. On Sunday, a report showed China’s factory activity unexpectedly contracted in July. The benchmark CSI 300 index retreated for a fourth week and tumbled 7% in July, its biggest monthly loss since March. It trailed the S&P 500 by 16 percentage points, giving up all of its outperformance in June when reopening euphoria swept the markets. Foreign investors sold 21 billion yuan ($3 billion) worth of stocks via the stock connect programs during the month, the most since March.

In addition to the Covid policies, the real-estate market remains a source of tension. Reports of several rescue proposals -- including to seize undeveloped land from distressed real estate-companies and to provide loans to support stalled property projects -- have floated around. Details may differ, but the underlying theme for all these plans is the same: saving unfinished projects to protect homeowners, instead of developers. Struggling developers such as Evergrande are left hanging.

2. To be, or not to be (in Taiwan), that is the question. US House Speaker Nancy Pelosi left for her Asia trip on Friday. Whether she’ll land in Taipei remains a mystery, even as her itinerary skipped any mention of a possible stopover in Taiwan. The talk between President Xi and Biden centered on Taiwan, but neither side described the discussion as “constructive.” One thing is crystal clear: Taiwanese stocks rose on the week and month, handily beating peers in Hong Kong and China. Investors appear to have largely dismissed the simmering geopolitical tension.

3. While bad news is bad news for markets in China, it apparently is good news for US investors. The US economy contracted for a second quarter. Whether it’s truly a recession or not, growth clearly has lost momentum. The Fed signaled it could slow down the pace of tightening after it delivered another 75bp rate hike to put the benchmark rate at 2.5%. It’s hardly as pivotal as some market observers claimed, because the markets’ pricing of the Fed’s policy rates for the remaining of the year barely changed, and is in line with what’s prescribed on the Fed’s dot plot. With financial conditions easing, the risk now is that inflation doesn’t come down as quickly as markets expect.

https://www.zerohedge.com/markets/chinese-stocks-underperform-sp-500-most-2016

Crime Has Become A Key Political Issue That's Stifling New York City's Post-Pandemic Growth

 When one looks at New York City's recovery from the pandemic lockdowns, it's hard to make the case that things are going swimmingly. The city is re-opening at a snail's pace, with some blocks (like the recently profiled block near the 59th St. subway) still "frozen" in peak-pandemic time.

And one of the key factors preventing the city from re-opening in a timely fashion has been the crime and the environment of criminal activity that has lingered since the days of the pandemic lockdowns and "peaceful protests", where many U.S. cities were nearly burned to the ground. 

As outlined in a new profile of the city by Bloomberg, violent incidents in New York have been in focus, emboldened by the hands-off law enforcement policies of Bill de Blasio and his administration over the last half decade. 

Police in many major cities feel like they can't do their jobs with Democratic leadership in place and citizens of said cities are continuing the exodus to the suburbs that started at the beginning of the pandemic. 

While Bloomberg is quick to spin that "incidents of violent crime remain at historic lows in New York City", they also point out that numerous "high-profile incidents in subway stations and tourist hubs" have left a bad taste in people's mouths when it comes to public safety. Young New Yorkers are seeing crime rise, instead of fall, for the first time in their lives, the report notes. 

And there's no doubt crime is in focus among those who live in New York, so something must be compelling citizens to take the issue far more seriously than they did several years ago.

In fact, about 75% of citizens said crime was a “very serious” problem in a February Quinnipiac University poll, marking the highest number since 1999. 

Crime in many major U.S. cities started to pick up as a result of the economic consequences of locking down, mixed with the riots and "protests" that took place after the George Floyd incident. 

"Washington D.C., Los Angeles, Chicago and other US cities saw murder rates climb to the highest point in over a decade, driven by gun violence," Bloomberg reported. It has caused many businesses - like Ken Griffin's Citadel - to abandon these cities and move to states like Florida and Texas. 

Crime has gotten so bad, it has also become a political talking point. Newly elected New York City Eric Adams was widely supported for his background in law enforcement and his willingness to give ground on reforming how policing is handled in the city. 

Lisa Miller, a political science professor at Rutgers University, commented: “We didn’t see people using crime [politically] at the local level a whole lot over the past 10 to 15 years because crime levels were historically low. What politicians do and whether they’re successful at it depends on how much people are generally frightened about walking around their communities.”

The article then goes on to question whether perception truly is reality, pointing out how media coverage surrounding crimes has changed and asking whether or not giving a bigger megaphone to the issue has created more of a problem than it is solving. 

The fact remains, however, that many younger generations in New York are seeing crime rise for the first time in their lifetimes. And the election of Eric Adams speaks to what is likely going to become a trend around the country: voters in cities are telling politicians that they demand law and order. 

But John Gramlich, who studies crime statistics at the Pew Research Center, concluded that it was all about perception: “If somebody feels unsafe, they’re probably not going to be comforted by the fact that overall crime in New York is lower today than it was 20 years ago. The feelings are important because it can translate into how people ultimately choose their leaders or vote on policies.”

https://www.zerohedge.com/markets/crime-has-become-key-political-issue-thats-stifling-new-york-citys-post-pandemic-growth

Wharton Study Finds 'Inflation Reduction Act' Has No Impact On Inflation

 by Jonathan Turley,

The Hill was thrown into near chaos this week when Senate Majority Leader Chuck Schumer (D-NY) and Sen. Joe Manchin (D-WV) unveiled the Inflation Reduction Act. 

Republicans charged that Manchin misled them into supporting a $280 billion chips and science bill - a bill they would have otherwise opposed. Others criticized the name of the bill, which contains a significant number of climate change items long sought by the Democrats.

Now, the respected Wharton School at the University of Pennsylvania has found that the Inflation Reduction Act would actually have no impact on inflation.

Manchin premised his change on the fact that the bill would reduce inflation despite raising taxes and expenditures. The Act would combat climate change, extend enhanced Obamacare subsidies, and reduce the budget deficit by roughly $300 billion.

Jon Huntley and John Ricco found that the bill “would reduce non-interest cumulative deficits by $248 billion over the budget window with no impact on GDP in 2031. The impact on inflation is statistically indistinguishable from zero.”

That is $52 billion less in deficit reduction than claimed by the Democrats and the review found the bill would actually “very slightly increase inflation until 2024 and decrease inflation thereafter.”

Wharton’s budget unit functions like an academic Congressional Budget Office in offering non-partisan budget analysis. At a time of growing orthodoxy and viewpoint intolerance, it remains an independent voice on budgetary issues.

For many, the Congress has become more bold in mislabeling legislation like an infrastructure bill that contained mainly non-infrastructure or “human infrastructure” provisions. Later a stripped down infrastructure bill was passed that was confined to actual infrastructure.

https://www.zerohedge.com/political/statistically-indistinguishable-zero-wharton-study-finds-inflation-reduction-act-has-no

Advanced MRI benefits patients with heart stiffening disease

 An advanced form of cardiac MRI, developed by academics at UCL in collaboration with the Royal Free Hospital, has for the first-time enabled clinicians to measure the effectiveness of chemotherapy in patients with the life-limiting condition 'stiff heart syndrome'.

Researchers say the breakthrough, published in the European Heart Journal, means doctors will now be able to better guide treatment strategies and, by doing so, improve patients' prognosis.

Light-chain cardiac amyloidosis (stiff heart syndrome) occurs when plaques of protein called amyloid build up in heart muscle, affecting its ability to pump blood, and without treatment can rapidly lead to heart failure and death.

However, assessing the condition has been difficult, as while clinicians can detect the presence of amyloid in the heart, there has been no safe test to measure the amount.

This has also meant there has been no way of measuring the therapeutic effect of chemotherapy -- the normal first line treatment.

A patient's response is currently assessed with indirect biological markers, but these do not measure the amount (or reduction) of cardiac amyloid -- the drug's ultimate target -- and doctors find the markers less useful when trying to assess second-line chemotherapy treatments.

To overcome this, UCL researchers at the National Amyloidosis Centre, have, for 10 years, been developing and refining Cardiovascular Magnetic Resonance (CMR) Extracellular Volume Mapping (ECV) for amyloid. This non-invasive technique enables clinicians to measure both the presence and amount of amyloid protein using MRI.

Now for the first time they have used the technology to evaluate the success of chemotherapy treatment, by assessing cardiac amyloid regression or progression.

For the study 176 patients with light-chain cardiac amyloidosis had Cardiovascular Magnetic Resonance with Extracellular Volume Mapping. CMR scans with ECV mapping were done at diagnosis, and then at six, 12 and 24 months after starting chemotherapy.

The advanced MRI technique allowed researchers to accurately measure the amount of amyloid protein in hearts, and, for the first-time ever, to measure the changes in response to chemotherapy on repeat scans. By measuring the changes they could detect which patients would have a better or worse prognosis.

Further, combining the results with blood tests for the disease, it was found almost 40% of patients had a substantial improvement (reduction) in amyloid deposition, something that was not thought to be possible before -- showing how effective chemotherapy can be.

First author, Dr Ana Martinez-Naharro (UCL Division of Medicine) said: "In this study we were assessing the ability and value of CMR to carry out ECV mapping to measure directly the changes in amyloid proteins in the heart in response to chemotherapy and how they correlate with the indirect markers that current exist.

"The scans and data made available using this technique, gave us the information to both see the amount of amyloid protein and also the regression in amyloid during the course of chemotherapy treatment.

"This is incredibly valuable for clinicians; knowing the amount, rather than just the presence of amyloid, means they can better guide treatment option, by more accurately deciding timing and protocol of second line chemotherapy treatments."

In the UK, there are about 4,000 to 6,000 amyloidosis patients, however there are many more who remain undiagnosed. The condition is more prevalent in men than women.

Senior author, Professor Marianna Fontana (UCL Division of Medicine), a British Heart Foundation (BHF) Clinical Fellow, said this UCL-developed MRI technique should now be used immediately to diagnose and assess all cases of light-chain cardiac amyloidosis.

"Since MRI scans are widely available, by developing the use of ECV mapping in a machine that already is used for these patients, we hope that its use can be made available to more patients to help improve their care.

"The aim would be to use these scans routinely for all patients with the disease to help doctors monitor the response to chemotherapy to help improve patient survival, which is very poor in patients who do not respond to treatment."

For the single-centre trial, patients were recruited and treated at the National Amyloidosis Centre, which is part of the UCL Division of Medicine and based at the Royal Free Hospital, London.

Professor Fontana added: "Twenty years ago, another MRI technique called T2*, was proven to be able to do the same thing for measuring the amount of iron in the heart in a condition called thalassemia.

"For the last two decades, it has been used to help monitor patients' response to treatment and allow doctors to make changes along the way. As a result, survival has improved for thalassemia.

"As T2* has changed the landscape for this condition, tracking changes using ECV mapping of the heart may completely change the landscape for patients with amyloidosis, with the potential of guide treatment and, in the process, lead to improvements in patient outcomes."

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Story Source:

Materials provided by University College London. Note: Content may be edited for style and length.

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Journal Reference:

1. Ana Martinez-Naharro et al. Cardiovascular magnetic resonance in light-chain amyloidosis to guide treatment. European Heart Journal, 2022 DOI: 10.1093/eurheartj/ehac363

https://www.sciencedaily.com/releases/2022/07/220728075914.htm

Schumer-Manchin deal injects ‘incredible amount of uncertainty into economy’: Cassidy

 Sen. Bill Cassidy (R-La.) on Sunday knocked the Inflation Reduction Act championed by Senate Majority Leader Charles Schumer (D-N.Y.) and centrist swing vote Sen. Joe Manchin (D-W.Va.), saying the bill could lead to a recession despite its sponsors’ claims that it will tamp down rising prices.

“It may be disinflationary by causing a recession. They’re interjecting an incredible amount of uncertainty into the economy just as we entered a recession,” Cassidy told Jonathan Karl on ABC’s “This Week.”

The measure is a scaled-down version of the Build Back Better Act that Manchin stymied last year.

The $670 billion reconciliation bill announced last week would invest in domestic energy, lower prescription drug costs, combat climate change and reduce the deficit by closing tax loopholes on wealthy individuals and corporations. 

“Much of what he says about this bill is just not true,” Cassidy said Sunday of Manchin’s comments earlier on the ABC program when the West Virginia Democrat defended his support of a climate and tax deal against claims that the measure could increase inflation over a year and a half.

Cassidy instead argued that the bill would raise taxes and lead to higher costs for consumers.

“I think what we’re doing is inducing [manufacturers] to move to Asia. You can have a disinflationary program by causing a recession. I think this is going to lead to a worse recession.”

https://thehill.com/homenews/sunday-talk-shows/3581545-cassidy-says-schumer-manchin-deal-injects-incredible-amount-of-uncertainty-into-to-the-economy/

12 states with BA.2.75 cases

 A dozen states have reported cases of the newest omicron subvariant BA.2.75 as of July 29, early disease surveillance data shows. 

The subvariant has numerous mutations that may make it more adept than BA. 5, the nation's dominant strain, at spreading quickly and evading immune protection. While it's still unclear whether BA.2.75 will compete against BA.5 or cause more severe illness, some experts contend the subvariant is not the next big one to fret over.

Below is a breakdown of U.S. states reporting BA.2.75 cases, based on a dashboard run by Raj Rajnarayanan, PhD, assistant dean of research and associate professor in the department of basic sciences at the New York Institute of Technology College of Osteopathic Medicine at Arkansas State University in Jonesboro. The dashboard uses data from GISAID, a global data-sharing platform for viruses.

California — 10

Washington — 9

Illinois — 4

Virginia — 3

North Carolina — 3 

Wisconsin — 2

New York — 2

Texas — 1

Nebraska — 1 

Iowa — 1

Delaware — 1

Arizona — 1

https://www.beckershospitalreview.com/public-health/12-states-with-ba-2-75-cases.html