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Safety and immunogenicity of SARS-CoV-2 recombinant spike protein vaccine

Jacob Scott

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Researchers in Cuba have presented the results of phase 1 and phase 2 clinical trials of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recombinant spike protein vaccine (Abdala). The vaccine is found to be safe, well-tolerated, and induces substantial humoral immune responses against SARS-CoV-2 among adults 19 to 80 years of age.


Study: Safety, tolerability, and immunogenicity of a SARS-CoV-2 recombinant spike protein vaccine: a randomised, double-blind, placebo-controlled, phase 1-2 clinical trial (ABDALA Study). Image Credit: Juan Gaertner/Shutterstock


The study was meant to evaluate the safety, tolerability, and immunogenicity of the newly developed vaccine administered intramuscularly in different strengths and vaccination schedules.


A pre-print version of the research paper is available on the medRxiv* server while the article undergoes peer review.


Background


The coronavirus disease 2019 (COVID-19) global pandemic continues to devastate the world even after two years of its initial origin in December 2019 from Wuhan, China. Obtaining safe and effective vaccines and implementing them with broad global coverage is the fastest and safest strategy to manage the consequences of this pandemic. Thus, clinical trials on multiple prophylactic vaccine candidates with accelerated designs are currently being carried out worldwide.


The Centre for Genetic Engineering and Biotechnology, Havana (Cuba), developed a vaccine candidate named Abdala, based on a recombinant receptor-binding domain (RBD) subunit of the spike protein produced in Pichia pastoris yeast and adjuvanted to alumina.


A randomized, adaptive, double-blind, placebo-controlled, phase 1-2 clinical trial was conducted to assess this vaccine candidate’s safety and immunogenicity profile.


Phase 1 Abdala study


A total of 132 subjects were included in the phase 1 trial, randomly distributed into two vaccination schedules (0-14-28 and 0-28-56 days) and three study groups for each schedule (placebo and two RBD strengths: 25ug and 50ug).


Blood samples were collected at day 0, before applying the first dose (baseline), at days 42 and 56 for the schedule 0-14-28 days, and at days 56 and 70 for the schedule 0-28-56 days to determine the level of anti-RBD IgG and neutralizing antibodies. Geometric mean titers (GMT) of anti-RBD IgG and neutralizing antibodies and the percentage of inhibition of RBD-ACE-2 binding were also determined.


The product was well tolerated. Adverse events were minimal, most resolved spontaneously in the first 24-48 hours without medication, and there were no withdrawals for this cause.


The primary immunogenicity outcome was the seroconversion rate of the IgG RBD-binding antibodies and was defined as at least a four-fold increase of antibody titers over the baseline.


In phase 1, none of the participants in the placebo groups were seroconverted, whereas high seroconversion rates were obtained for both strengths of RBD/vaccination schedules.


At day 56 (28 days after the third dose of the short vaccination schedule, 0-14-28 days), seroconversion of anti-RBD IgG was seen in 95.2% of the participants (20/21) for the 50ug group and 81% of the participants (17/21) for the 25ug group, whereas neutralizing antibodies to SARS-CoV-2 were seen in 80% of the participants (8/10) for the 50ug group and 94.7% of the participants (18/19) for the 25ug group.


For the long schedule, at day 70 (14 days after the third dose), seroconversion of anti- RBD IgG was seen in 100% of the participants (21/21) for the 50ug group and 94.7% of the participants (18/19) for the 25ug group, whereas neutralizing antibodies to SARS-CoV-2 were seen in 95 % of the participants (19/20) for the 50ug group and 93.8% of the participants (15/16) for the 25ug group.


Phase 2 Abdala study


After an interim analysis of the phase 1 trial results and given the complex epidemiological situation resulting from the COVID-19 pandemic where it was necessary to immunize people in the shortest possible time, the team strategically decided to continue towards phase 2 of the trial with the three study groups of the short vaccination schedule (0-14-28 days).


Therefore, phase 2 included 660 new subjects, to which were added the 66 subjects evaluated in a similar vaccination scheme during the first trial (726 subjects in total; 242 in each study group).


In phase 2, only the short scheme (0-14-28 days) was evaluated during the interim analysis. Blood samples were collected at day 0, day 42, and day 56 (14 and 28 days after the third dose).


On day 56, seroconversion of anti-RBD IgG was seen in 89.2% of the participants (214/240) for the 50ug group, 77.7% of the participants (185/238) for the 25ug group, and 4.6% in the placebo group (11/239); whereas neutralizing antibodies to SARS-CoV-2 were seen in 97.3% of the participants (146/150) for the 50ug group and 95.1% of the participants (58/61) for the 25ug group.


Three dose schedule of Abdala vaccine induces high immune responses in adults 19-80 years old


The safety and immunogenicity analyses demonstrated that three doses of Abdala at different strengths and different immunization schedules were safe and induced high immune responses in adults 19 to 80 years of age, including neutralizing antibodies correlated with the anti-RBD IgG response.


The incidence of adverse reactions in the 25ug and 50ug groups were similar, indicating no dose-related safety issue. The adverse reactions reported were minimal.


The team highlights that although most of the COVID-19 vaccines already in use are administered mainly in schedules of two doses and the three-dose schedule can be thought of as complicated and time-consuming, the short immunization schedule proposed in this trial (0-14-28 days) would allow for only one month the vaccination regimen to be completed with a good immunogenic profile. Potentially a third dose instead of only two doses in this short time would be more favorable.


Phase 2 results were consistent with those obtained previously in phase 1 trial. They confirmed the favorable immunogenic profile of the Abdala vaccine with better results and risk-benefit ratio for the 50ug dose group.


The vaccine’s better immunological performance was obtained in the age group 19-54 years compared to the older individuals aged 55-80 years. Age is considered an important factor influencing the immune response to vaccines, and this effect has been found for several vaccines where older people have lower antibody levels. Nevertheless, more than 80% of the subjects were seroconverted in the study. Other COVID-19 vaccines have shown lower responses in older individuals when compared with the youngest ages.


“The level of in vitro antibody response does not necessarily correlate with health outcomes, i.e., seroconversion does not mean complete protection against a disease, and non-seroconversion is not necessarily associated with susceptibility, not to mention that antibody levels decline over time, but seronegative individuals may still be protected through other immune mechanisms, as shown, for example, after hepatitis B vaccination” the team highlights.


Pearson’s linear correlation analyses found positive and highly significant correlations between different immunogenicity variables, indicating that the immune response for the vaccine is potent both in quantity and the quality of the antibodies elicited.


*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:
Hernandez-Bernal F., et al. (2021) Safety, tolerability, and immunogenicity of a SARS-CoV-2 recombinant spike protein vaccine: a randomised, double-blind, placebo-controlled, phase 1-2 clinical trial (ABDALA Study). medRxiv. doi: https://doi.org/10.1101/2021.11.30.21267047, https://www.medrxiv.org/content/10.1101/2021.11.30.21267047v2

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Unraveling How Strigoractone Hormone Regulates Massive Gene Networks Controlling Plant Growth

Jacob Scott

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As sessile organisms, plants have to continually adapt their growth and architecture to the ever-changing environment. To do so, plants have evolved distinct molecular mechanisms to sense and respond to the environment and integrate the signals from outside with endogenous developmental programs.

New research from Nitzan Shabek’s laboratory at the UC Davis College of Biological Sciences, published in Nature Plants, unravels the underlying mechanism of protein targeting and destruction in a specific plant hormone signaling pathway.

Our lab aims at deciphering sensing mechanisms in plants and understanding how specific enzymes function can be regulated at the molecular levels. We have been studying a new plant hormone signal, strigolactone, that governs numerous processes of growth and development including branching and root architecture.”

Nitzan Shabek, assistant professor of biochemistry and structural biology, Department of Plant Biology

The work stems from a study by Shabek, published in Nature in 2018, unravelling molecular and structural changes in an enzyme, MAX2 (or D3) ubiquitin ligase. MAX2 was found in locked or unlocked forms that can recruit a strigolactone sensor, D14, and target for destruction a DNA transcriptional repressor complex, D53. Ubiquitins are small proteins, found in all eukaryotes, that “tag” other proteins for destruction within a cell.

To find the key to unlock MAX2 and to better understand its molecular dynamics in plants, postdoctoral fellows Lior Tal and Malathy Palayam, with junior specialist Aleczander Young, used an approach that integrated advanced structural biology, biochemistry, and plant genetics.

“We leveraged structure-guided approaches to systemically mutate MAX2 enzyme in Arabidopsis and created a MAX2 stuck in an unlocked form”, said Shabek, “some of these mutations were made by guiding CRISPR/Cas9 genome editing thus providing us a discovery platform to study and analyze the different signaling outputs and illuminate the role of MAX2 dynamics.”


They found that in the unlocked conformation, MAX2 can target the repressor proteins and biochemically decorate them with small ubiquitin proteins, tagging them for destruction. Removing these repressors allows other genes to be expressed – activating a massive gene network that governs shoot branching, root architecture, leaf senescence, and symbiosis with fungi, Shabek said.

Sending these repressors to the proteasome disposal complexes requires the enzyme to relock again. The team also showed that MAX2 not only target the repressors proteins, but once it is locked the strigolactone sensor itself gets destroyed, returning the system to its original state.

Finally, the study uncovered the key to the lock, an organic acid metabolite that can directly trigger the conformational switch.

“Beyond the implication in plants signaling, this is the first work that placed a primary metabolite as a direct new regulator of this type of ubiquitin ligase enzymes and will open new avenues of study in this direction,” Shabek said.

Additional coauthors on the paper are specialist Mily Ron and Professor Anne Britt, Department of Plant Biology. The study was supported by NSF CAREER and EAGER grants to Shabek. X-ray crystallography data was obtained at the Advanced Light Source, Lawrence Berkeley National Laboratory, a U.S. Department of Energy user facility.

Source:
Journal reference:

Tal, L., et al. (2022) A conformational switch in the SCF-D3/MAX2 ubiquitin ligase facilitates strigolactone signalling. Nature Plants. doi.org/10.1038/s41477-022-01145-7.

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UrFU Sociologists Identify Digital Fears Among Young People

Jacob Scott

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Sociologists at the Ural Federal University (UrFU) have identified digital fears among young people. According to experts, these are additional fears that do not replace, but complement and reinforce traditional ones. They emerged against the background of uncertainty, the growth of forces beyond human control. Developed emotional intelligence, creativity, and the ability to collaborate help to overcome them.

In the study, sociologists interviewed 1,050 people aged 18-30. Respondents were asked to assess which digital risks concern them most. The study was launched in 2020 and the results were published in April 2022 in the Changing Societies & Personalities journal.

The first group of fears is influence and control. It touches on the problem of interference with privacy by technical means. This category is the most significant for young people: 55.8% are afraid of total control by means of video-surveillance and monitoring software on their mobile devices. 48.5% of respondents believe they are at risk of wiretapping, tracking content in social networks, and inability to keep correspondence secret.”

Natalia Antonova, Professor, Department of Applied Sociology, UrFU

45.8% of young people fear the manipulative influence of the media and an increase in fake news. At the same time, only 27.8% and 18.1% of respondents are concerned about microchipping and genetic manipulation, respectively. It is likely that these threats seem more controllable, both from the individual (through control of food choices, medical procedures, etc.) and from government programs, the researchers believe.

The second group of concerns is crime and security. Here young people are wary of illegal actions using digital technology.

“One of the main fears of 56% of young people is the security of personal data. This is related both to the growth of personal information in social networks and messengers, and to the growth of hacker attacks and viruses. 42.9% of young citizens are afraid of Internet fraudsters, and 25.8% are afraid of losing important information, including smashing their phones, not saving data, forgetting their passwords, or being without an Internet connection,” explains Sofia Abramova, Associate Professor at the Department of Applied Sociology at UrFU.

The third group of fears is based on changes in the way and pace of life, ways of interaction. Thus, 28.4% of respondents indicate a constant lack of time, the acceleration of communications, and worries about not being able to complete all tasks in time. Respondents are also concerned about the growth of online communications and communications with electronic systems (bots, autoresponders, product systems, etc.).

“As a result, 15.3% of young people raise problems related to increasing social distrust against the background of increasing dependence of human life and health on other people and electronic systems: in public transport, planes, elevators, medical intervention,” explains Sofia Abramova.

Respondents also fear the negative consequences of technological development. For example, 22.2% of young citizens fear the robotization of labor processes and the displacement of humans by robots. 14.6% speak directly about negative emotions in relation to the expansion of artificial intelligence.

The fifth type of fear is social inequality. Young people negatively assess the growth of inequality in access to information resources and technology, the exclusion of citizens from the economy depending on the level of digital competence and education, and age. As a result, they fear that benefits will be distributed more and more unequally, both among the inhabitants of the country and between countries.

“It is noteworthy that young people are simultaneously afraid of total surveillance via phone and afraid of being left without mobile devices. Fears shape the irrational behavior of the digital generation, entailing serious transformations in everyday life,” says Natalia Antonova.

Source:
Journal reference:

Abramova, S.B., et al. (2022) Digital Fears Experienced by Young People in the Age of Technoscience. Changing Societies & Personalities. doi.org/10.15826/csp.2022.6.1.163.

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Study demonstrates increased incidence of SARS-CoV-2 Omicron breakthrough infection in cancer patients

Jacob Scott

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In a recently published article in the journal Cancer Cell, scientists have demonstrated the incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in cancer patients residing in Austria and Italy. The study reveals an induction in Omicron breakthrough infections in patients with hematologic and solid cancers.

Study: Enhanced SARS-CoV-2 breakthrough infections in patients with hematologic and solid cancers due to Omicron. Image Credit: Lightspring/Shutterstock

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of the coronavirus disease 2019 (COVID-19) pandemic, has been found to cause severe infections in immunocompromised patients, including cancer patients. Moreover, a relatively lower level of neutralizing antibodies in response to COVID-19 vaccines has also been observed in cancer patients, especially those receiving B cell-targeting therapies.

The emergence of SARS-CoV-2 variants with improved immune fitness, such as delta and Omicron variants, has caused a sharp increase in breakthrough infections even in fully vaccinated individuals. However, the vaccines still show high protective efficacy against severe and fatal infections. COVID-19 vaccines have shown acceptable efficacy against severe disease, even in Omicron-infected cancer patients. However, the isolation and quarantine measures associated with SARS-CoV-2 infection may impair the routine administration of anticancer therapy, which can reduce the survival prognosis in cancer patients.

In the current study, the scientists have assessed the incidence of SARS-CoV-2 infection in cancer patients throughout the pandemic.

Study design

The study included 3,959 cancer patients, of whom 77% had solid cancer, and 23% had hematologic cancer. About 69% of the patients did not receive any anticancer treatment at the time of COVID-19 vaccination. Regarding vaccine coverage, about 85% of the patients had received at least one vaccine dose, and 15% remained unvaccinated. The incidence of SARS-CoV-2 infection in these patients was assessed between February 2020 and 2022.

Important observations

SARS-CoV-2 infection was detected in about 24% of the patients during the study period. During the delta-dominated wave, vaccine breakthrough infection was observed in 43% of the patients. In contrast, a significantly higher percentage of breakthrough infection (70%) was observed among the patients during the Omicron-dominated wave. During both delta and Omicron waves, cancer patients receiving systemic anticancer treatment showed a significantly higher percentage of breakthrough infection than those not receiving treatment (83% vs. 56%).

Regarding disease severity irrespective of vaccination status, a higher frequency of COVID-19-related hospitalization was observed during the delta wave compared to that during the Omicron wave. However, a relatively shorter duration of hospital stay was observed in vaccinated patients compared to that in unvaccinated patients. In addition, only 9% of patients with breakthrough infections were admitted to the intensive care unit (ICU). This highlights the protective efficacy of COVID-19 vaccines against severe disease.

Humoral immune response to vaccination

To determine vaccine-induced antibody response against delta and Omicron variants, the scientists measured blood levels of anti-delta and anti-Omicron spike receptor-binding domain (RBD) antibodies in a total of 78 cancer patients. In the analysis, they also included 25 healthcare workers as controls.

In response to vaccination, healthcare workers showed higher levels of total anti-spike antibodies compared to cancer patients. The lowest level of wildtype RBD-specific antibodies was observed in hematologic cancer patients receiving B cell-targeted treatment, followed by hematologic cancer patients not receiving B cell-targeted treatment and patients with solid tumors. A similar trend was observed for delta- and Omicron-specific spike RBD antibodies.

The serum samples collected from hematologic cancer patients without B cell-targeted treatment and solid tumor patients significantly inhibited the interaction between wildtype/delta RBD and angiotensin-converting enzyme 2 (ACE2; host cell receptor for viral entry). However, a significantly lower level of inhibition was observed for patients receiving B cell-targeted treatment. Importantly, a marked reduction in inhibition of Omicron RBD – ACE2 interaction was observed for all patients with solid tumors and hematologic cancer.

Study significance

The study demonstrates an increased incidence of vaccine breakthrough infections but a reduced disease severity among patients with solid tumors and hematologic cancer during the Omicron wave compared to the delta wave.

The study also highlights that COVID-19 vaccine-induced antibody response is lower in cancer patients than in healthy individuals. The reduction in antibody response is highest among hematologic patients receiving B cell-targeted treatment. Overall, a significant impairment in vaccine-induced Omicron neutralization has been observed in cancer patients.

Journal reference:
Mair, M. et al. (2022) “Enhanced SARS-CoV-2 breakthrough infections in patients with hematologic and solid cancers due to Omicron”, Cancer Cell. doi: 10.1016/j.ccell.2022.04.003. https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00165-9

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