Nanoparticles—Drug Loading and Release

Drug delivery can affect drug pharmacokinetics, absorption, distribution, metabolism, duration of therapeutic effect, excretion, and toxicity.  Nanoparticles (NPs) are thought to have potential for novel drug delivery and release purposes.

Critical considerations for a successful nano based drug delivery system include its ability:

• To target specific tissues and cell types 
• Endocytosis (uptake into the cells)
• Targeting agent (address tags)
• To escape from the biological particulate filter 
• Mononuclear Phagocyte System (clearance of unwanted particulate material)
• Clearance avoidance 
• Main NP research question—how is particulate material recognized and cleared?

In this article, we will cover the above four highlighted areas.

Figure 1. Endocytosis (Credit: Mariana Ruiz Villarreal LadyofHats - Own work)

Biological Particulate Filter 

Cells of Mononuclear Phagocytic System (MPS) are cells responsible for the clearance of particulate matter such as bacteria, fungi, viruses, and dying cells from the circulation.

NP association with the host highly evolved MPS is a function of particle opsonization upon contact with blood and rapid recognition of these opsonins via the MPS.^[113,115] This is particularly observed in structurally distinct fenestrated vasculature via liver Kupffer cells and splenic macrophages.^[127,128]

As soon as nanoparticles enter to the bloodstream, they are prone to aggregation and protein opsonization (protein binding to nanoparticle surface as a tag for immune system recognition). The opsonized nanoparticles could be cleared from the bloodstream by phagocytosis or filtration in the liver, spleen, and kidney. This rapid and non-specific clearance by the immune system results in decreased retention time and thus limits bioavailability. 

To design improved NPs for drug delivery, we need to consider how to  escape from such biological particulate filter and the like, which include:

• Scavenger endothelial cells
• Cells responsible for the avid clearance of macromolecules and nanoparticles from the blood circulation
• Liver sinusoidal endothelial cells (LSECs)
• Cells largely responsible for removing viruses and small immune complexes from blood
• Are only pinocytic (vs phagocytotic)
• Kupffer cells (KCs—localized in liver)
• Represent the largest population of mononuclear phagocytes in the body.
• Should virions be aggregated, by whatever means, they may be too large for pinocytic uptake and would then qualify for phagocytic uptake by KC but not LSEC (see Fig. 1).
• Spleen
• Spleen is the 2nd largest unit of the mononuclear phagocyte system
• The spleen is a center of activity of the mononuclear phagocyte system and is analogous to a large lymph node
• Cells lining the lymph sinuses

Clearance Avoidance Design

Nanoparticle delivery vehicles designed to either avoid or specifically harness this host recognition system (i.e., MPS) could improve payload delivery, reduce inflammatory effects and improve drug efficacy. 

The particle size and surface properties of NPs can be manipulated to avoid rapid clearance by phagocytic cells, allowing both passive and active drug targeting.

Design considerations of clearance avoidance include:

• Surface modification 
• By decorating the nanoparticle surface with polyethylene glycol (PEG), carbohydrates, acetyl groups, or protein moieties (arginine-glycine-aspartate (RGD) peptide, albumin), retention time can be altered [6]. 
• However, such surface modification can also alter the recognition ability for targeted delivery. Thus, the cleanability and biodistribution of therapeutic nanoparticles should be well concerned during the design process.
• Size consideration
• Size is one important factor playing role in controlling circulation and biodistribution of therapeutic nanoparticles. 
• Nanoparticles smaller than 10 nm, can be easily cleared by physiological systems (filtration through the kidney), while particles larger than 200 nm may be cleared by phagocytic cells in the MPS.
• Accordingly, therapeutic nanoparticles with a size of <100 nm have longer circulation time in the bloodstream.^[134]
• For example, many studies reported that therapeutic nanoparticles in 20–200 nm size showed a higher accumulation rate in tumors because they cannot be recognized by the MPS and filtrated by the kidney.^[135-137]

Advantages of Nanoparticle Applications

Drugs with very low solubility possess various biopharmaceutical delivery issues including:

• Limited bio accessibility after intake through mouth
• Less diffusion capacity into the outer membrane
• Require more quantity for intravenous intake 
• Unwanted after-effects preceding traditional formulated vaccination process. 

However all these limitations could be overcome by the application of nanotechnology approaches in the drug delivery mechanism.  

The shape and size of nanoparticles affects how cell in the body “see” them and thus dictate their distribution, toxicity, and targeting ability.

Most importantly, nanoparticles can cross the BBB providing sustained delivery of medication for diseases that were previously difficult to treat.[133]

Drug designing at the nanoscale has been studied extensively and is by far, the most advanced technology in the area of NP applications because of: 

• Potential for administration through various routes, including oral, pulmonary, nasal, parenteral, intraocular etc.
• The possibility to modify their properties like solubility, drug release profiles, diffusivity, bioavailability and immunogenicity by incorporating nanoparticles
• Adjustments in nanostructures size, shape, hydrophobicity, and surface changes can further enhance the bioactivity of these nanomaterials.
• Nanostructures stay in the blood circulatory system for a prolonged period and enable the release of amalgamated drugs as per the specified dose. Thus, they cause fewer plasma fluctuations with reduced adverse effects.
• Being nanosized, these structures penetrate in the tissue system, facilitate easy uptake of the drug by cells, permit an efficient drug delivery, and ensure action at the targeted location. 
• The uptake of nanostructures by cells is much higher than that of large particles with size ranging between 1 and 10 µm. 
• Hence, they directly interact to treat the diseased cells with improved efficiency and reduced or negligible side effects.
• NPs reportedly aid in preventing drugs from being tarnished in the gastrointestinal region and help the delivery of sparingly water-soluble drugs to their target location. 
• Nanodrugs show higher oral bioavailability because they exhibit typical uptake mechanisms of absorptive endocytosis.
• For instance, thymoquinone, a bioactive compound in Nigella sativa, is studied after its encapsulation in lipid nanocarrier. After encapsulation, it showed sixfold increase in bioavailability in comparison to free thymoquinone and thus protects the gastrointestinal stuffs.
• Ability to reach the smallest capillary vessels, due to their tiny volume, and to penetrate the tissues either through the paracellular or the transcellular pathways.

Figure 2. Elements of nanotechnology, which are utilized in therapeutic applications (source: [134])

Research Areas of Nanotechnologies in Drug Delivery

Polymeric nanoparticles can be categorized into nanospheres and nanocapsules both of which are excellent drug delivery systems. Likewise, compact lipid nanostructures and phospholipids including liposomes and micelles (first generation nanoparticle-based lipid systems) are very useful in targeted drug delivery.

The primary goals for research of nanotechnologies in drug delivery include:

• More specific drug targeting and delivery
• Reduction in toxicity while maintaining therapeutic effects
• Greater safety and biocompatibility
• Faster development of new safe medicines

Drug Loading

Choice of an ideal nano-drug delivery system is decided primarily based on the biophysical and biochemical properties of the targeted drugs being selected for the treatment.

There are two ways through which nanostructures deliver drugs:^[126]

• Passive
• Drugs are incorporated in the inner cavity of the structure mainly via the hydrophobic effect
• When the nanostructure materials are targeted to a particular sites, the intended amount of the drug is released because of the low content of the drugs which is encapsulated in a hydrophobic environment.
• Self-delivery
• Drugs intended for release are directly conjugated to the carrier nanostructure material for easy delivery.
• In this approach, the timing of release is crucial as the drug will not reach the target site and it dissociates from the carrier very quickly, and conversely, its bioactivity and efficacy will be decreased if it is released from its nanocarrier system at the right time.

Nanostructures could be utilized as delivery agents by encapsulating drugs or attaching therapeutic drugs and deliver them to target tissues more precisely with a controlled release.^[129,130]

The main benefits of these nanoparticles are associated with their surface properties; as various proteins can be affixed to the surface.

Moreover, adjustments in nanostructures size, shape, hydrophobicity, and surface changes can further enhance the bioactivity of these nanomaterials.

>

Figure 3.  Inductive drug release by temperature difference

Figure 4.  Drug release from polymeric gels. (A) Encapsulated drug released concomitant with gel degradation. (B) Release by linker cleavage of covalently tethered drug, followed by gel degradation.

Controlled Drug Release

Controlled and sustained drug release at the target site, improving the therapeutic efficacy and reducing side effects. 

Nanostructures can stay in the blood circulatory system for a prolonged period and enable the release of drugs as per the specified dose. Moreover, pH-, thermo-, ultrasound-, or light-sensitive nanomaterials allow for controlled NP dissociation and triggered drug release. The combination of these approaches can further improve specificity and efficacy of NP-based drug delivery and brings the development of a ‘smart’ or ‘intelligent’ nanosized drug deliver system a major step forward.

How the hydrogel releases the drug is often essential to achieve desirable therapeutic outcomes, and the required duration of drug availability (short term versus long term) and its release profile (continuous versus pulsatile) depend on the specific application.^[6] 

With consistent efforts, researchers have strived to engineer nanosized hydrogels by modifying their physical and chemical properties, referring to them as ‘smart’ or ‘intelligent’ hydrogels since they respond to external stimuli like temperature (Fig. 3), pH, light, magnetic and electric fields, ionic strength, or enzymatic environment.

Some NP-based drug deliver system with tunable drug release designs will be discussed in the below subsections.

Ultrasound

Natural biological processes are intricately controlled by the timing and spatial distribution of various cues. To mimic this precise level of control, the physical sizes of gold nanoparticles are utilized to sterically entrap them in hydrogel materials, where they are subsequently released only in response to ultrasound. These nanoparticles can transport bioactive factors to cells and direct cell behavior on-demand.^[13]

Drug-Releasing Linkers

Most biodegradable drug-delivery implants encapsulate a drug within gels of limiting pore size that retards diffusion, and release the drug concomitant with hydrolytic degradation—often of ester bonds—of the polymer (Fig. 4A).^[131,132]

In contrast, for a Tetra-PEG gels using drug-releasing linkers, they required a porous gel that readily allows diffusion, is substantially stable over the duration of drug release, and degrades subsequent to release of the drug (Fig. 4B).^[21]

Smart Targeting of Nanoparticles

One of the more prevalent targeting ligands conjugated to nanoparticles are small molecules. The major advantages of using a small molecule as targeting ligand is its stability, ease of conjugation with nanoparticles, and the potential low cost, assuming it can be chemically synthesized with high yield.

Existence of a multitude of preparation methods of polymeric nanoparticles can control the release characteristics of incorporated therapeutic agents, which allows the delivery of a higher concentration of agents to the target location. 

Moreover, the surface of polymeric nanoparticles could be easily modified and functionalized with a specific recognition ligand which increases the specificity of therapeutic agents in targeted tissue.

In a review article,^[140] it  illustrates methods of ligand-nanoparticle functionalization, provides a cross-section of various ligand classes, including small molecules, peptides, antibodies, engineered proteins, or nucleic acid aptamers, and discusses some unconventional approaches currently under investigation.

In this article, we will use oligonucleotides for illustration.

Oligonucleotides—Good ligands for NP Functionalization

Oligonucleotides are short DNA or RNA molecules, oligomers. The various types of oligonucleotides do not only play essential roles within living organisms but also have found widespread applications in different research areas ranging from antisense therapy and siRNA delivery to hierarchical self-assembly for the creation of new materials.^[139] Their inherent properties of accurate addressability and programmability, high target specificity, as well as ease of synthesis and functionalization have made oligonucleotides attractive ligands for NP functionalization.^[138]

Chemically modified oligonucleotides, such as locked nucleic acids (LNA) or peptide nucleic acids (PNA), have been developed to increase target binding affinity through increased base-stacking and to be enriched with high stability toward nuclease digestion, respectively. 

Taking into account the versatility of oligonucleotides, it is unsurprising, that oligonucleotides as ligands to coat NPs play an important role in the function of nanoparticulate systems. 

Over the last two decades DNA-coated NPs have become increasingly important for applications in nanomedicine. The DNA ligand shell stabilizes the NP core both through sterical and electrostatic interactions resulting in NPs that are highly stable in a variety of complex media. Different conjugation strategies based on direct oligonucleotide chemisorption, physisorption, or involving coupling chemistry have been developed.

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124. Engineering the Dynamics of Cell Adhesion Cues in Supramolecular Hydrogels for Facile Control over Cell Encapsulation and Behavior
125. Nanoparticles in the clinic: An update post COVID‐19 vaccines
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Coronavirus Deaths Worldwide by Country (09/17/2021)

The below scattered charts were drawn with:

• x-axis: Confirmed Cases per million (Total)
• y-axis: Deaths per million (Total) 

based on the data from [1].  Note that only the top 50 countries with the highest deaths per million are used in the chart.

Based on a comparison of coronavirus deaths in 206 countries relative to their population, Peru had the most losses to COVID-19 up until September 17, 2021. As of the same date, the virus had infected over 227 million people worldwide, and the number of deaths had totaled more than 4.6 million.

Chart 1.  Scattered chart (x: confirmed cases and y: deaths; Source: [1])

Chart 1

In chart 1, only three countries stand out:

• USA
• Brazil
• Peru

Among the three countries, Peru suffered the highest death rate vs confirmed cases, which may be due to combinations of reasons.  For example,

• Poorer healthcare system
• More immune-comprised population

However, based on [2], Peru's confirmed cases are likely underestimated, which it means that its correct data point position on the chart should be shifted horizontally to the right.

Chart 2

After removing 3 outliers (USA, Brazil and Peru) from Chart 1, Chart 2 was drawn with other 47 countries.  Among the 47 countries, the following countries stand out:

• Ireland
• It has less confirmed cases and it has the least loss among its infected people, which probably are due to its better healthcare system and maybe better policy responses to COVID-19. 
• Hungary, Bosnia and Herzegovina, North Macedonia
• 3 European countries suffered the highest death rate vs confirmed cases.
• United Kingdom, France, and Russia
• Among these 3 countries, UK has the highest death rate vs confirmed cases and Russia has the lowest death rate vs confirmed cases.

Chart 2.  Scattered chart (x: confirmed cases and y: deaths; Source: [1])

References

1. Coronavirus (COVID-19) deaths worldwide per one million population as of September 17, 2021, by country
2. COVID-19 figures are likely underestimated in Peru (07/27/2020)
• A new government study suggests that around one-quarter of Lima's population has been infected with COVID-19
3. Cabbage and fermented vegetables: From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19
• In Switzerland, the French- and Italian-speaking cantons have a far higher death rate than the German-speaking ones (Office fédéral de la santé publique, Switzerland).

Sir Jeremy James Farrar—The Coronavirus Is Here to Stay. But, What's Next?

The below is a tweeter thread that Kai Kupferschmidt (a science journalist and molecular biologist) put together of the conversation between him and Sir Jeremy James Farrar (a British medical researcher and director of the Wellcome Trust since 2013) on a very important topic:

At least in Europe, "what you're witnessing, I think at the moment is the shift from epidemic/pandemic state into an endemic state”, Farrar said. 

“And none of us are really quite sure what that endemic state is going to look like.”

Source: Yalemedicine.org

Endemic State 

But what level of disease and death is deemed acceptable and thus what “endemic” looks like is going to differ from society to society. Farrar has been calling for an honest debate about this:  “I think all countries are going to have to have this debate.”

This goes far beyond Europe, of course. “If you are New Zealand, I don't know how you plot your exit from this” Farrar told me. “China's in an even harder position, because it's got 1.4 billion people and its vaccines are not as effective as the vaccines used in Europe.”

The problem: "I think that politicians across the world are sort of pretending you can have your cake and eat it: You can have zero deaths, no control measures, vaccinate if you want to or not vaccinate - and it will all end. 

I just don't think that's realistic.”

How Bad a Country Can Tolerate the Level of Death

This is a crucial point: A country with a given vaccination coverage will have to accept either a certain level of death or a certain level of restrictions (or a mix). 

Different countries may end up with different set points for endemic #covid19.

The countries that are likely worst off in the early part of this endemic phase are those like US where immunizations AND control measures like masking have become polarized. 

With low immunization levels and few restrictions, they are stuck with high levels of disease and death.

What's That Level for UK?

I asked Farrar about the situation in the UK where about 100 people were dying a day of #covid19. What level of #covid19 deaths did he think the UK specifically might have to accept?

He said he was for lockdowns last year, "because the health consequences were so profound, 1000 deaths a day, 1200 deaths a day in the UK. It was just unacceptable, in my view, and the health system came very close to collapse … 

But we're in a different world with vaccination.”

Without vaccines, there would be >1000 deaths a day in UK, he says. "That's how dramatic the impact has been.”

But: "We're going to have to accept a certain number of ill health and deaths from COVID, as we do for malaria, as we do from flu. The question is, what is that level?"

So what number: "I think around 100 deaths a day, throughout the year, 30,000 deaths a year, in the current situation with the current vaccines, current treatments, current capacity within the system, I think is a level that would have to in the end be acceptable."

Two Big Problems

There are two big problems with all this, of course, that he acknowledges: 

1. Long-term sequelae of #covid19 (long covid)

2. Letting the virus replicate means letting new variants evolve

What Are the Key Takeaways?

So what are the key takeaways?

1. Vaccinate, vaccinate, vaccinate: That is what gets you out of the worst of this

2. If you don’t vaccinate enough, you will end up with tough measures or a lot of deaths, probably both.

3. Be honest about this in public.

And, on the global scale:

Share the vaccines, so that all countries can vaccinate, vaccinate, vaccinate.

Every country needs to protect the most vulnerable. 

See Also

1. BBC Discovery — Covid origins: The science
2. "We Must Learn To Live With It" - WHO's EU Chief Admits COVID Isn't Going Anywhere

Forest Therapy and Shinrin Yoku (森林浴)

Video 1.  Forest Bathing | Shinrin-Yoku | Healing in Nature | Short Documentary (YouTube link)

Forest therapy, a term refer to immersing yourself in the atmosphere of the forest, can be incorporated as a stress-reduction strategy.^[2] The practice began in Japan. Back in the early 1990s the Japanese Ministry of Agriculture, Forestry and Fisheries coined the term Shinrin-yoku — which translates roughly as forest bathing.

The idea that spending time in nature is good for our health is not new. Most of human evolutionary history was spent in environments that lack buildings and walls. Our bodies have adapted to living in the natural world.

Video 2. Trees in the Amazon that make their own rain clouds (YouTube link)

Benefits of Forest Bathing

"Forest bathing could be considered a form of medicine," Philip Barr says, a physician who specializes in integrative medicine at Duke University. "And the benefits of nature can be accessed so simply."

There's a growing body of evidence that the practice can help boost immunity and mood and help reduce stress.

One study published in 2011 compared the effects of walking in the city to taking a forest walk. Both activities required the same amount of physical activity, but researchers found that the forest environment led to more significant reductions in blood pressure and certain stress hormones.

There's another factor that might help explain the decline in blood pressure: Trees release compounds into the forest air that some researchers think could be beneficial for people. Some of the compounds are very distinctive, such as the scent of cedar. 

Back in 2009, Japanese scientists published a small study that found inhaling these tree-derived compounds — known as phytoncides — reduced concentrations of stress hormones in men and women and enhanced the activity of white-blood cells known as natural killer cells .

A study found inhalation of cedar wood oils led to a small reduction in blood pressure. These are preliminary studies, but scientists speculate that the exposure to these tree compounds might enhance the other benefits of the forest.

References

1. Trees Are More than Just Trees: the Good, the Bad, and the Ugly
2. Forest Bathing: A Retreat To Nature Can Boost Immunity And Mood
3. Acute effects of walking in forest environments on cardiovascular and metabolic parameters
4. Autonomic responses during inhalation of natural fragrance of Cedrol in humans
5. Why Forest Therapy Can Be Good for Your Body and Mind
6. The physiological effects of Shinrin-yoku (taking in the forest atmosphere or forest bathing): evidence from field experiments in 24 forests across Japan
7. Physiological effects of Shinrin-yoku (taking in the atmosphere of the forest)--using salivary cortisol and cerebral activity as indicators
8. Acute effects of walking in forest environments on cardiovascular and metabolic parameters
9. Effect of Natural Compounds on NK Cell Activation
• NK cell-activating compounds: vitamins belonging to classes A, B, C, D, and E, polysaccharides, lectins, and a number of phytochemicals

Roles of Antibodies vs. T Cells in Protecting against COVID-19

 On 09/02/2021, Professor Akiko Iwasaki has shared her insights on answering the below question:^[4]

The roles of antibodies vs. T cells in controlling primary infection, reinfection, and vaccine-mediated protection?

Figure 1.  COVID-19 vaccines immune activation modes (Source: [5])

Summary of Professor Akiko Iwasaki's Comments

Q: If B cells are needed to control primary infection
A: 

• B cells are not necessary for controlling primary SARS-CoV-2 infection.  
• However, in mice that have neither T cells nor B cells, SARS-CoV-2 persisted with no sign of clearance. Thus, innate immunity is insufficient, and adaptive immunity is required to control primary infection.
• Which implies that defects in T and B cell immunity predispose people for chronic COVID infection

Q: If CD4 (helper) vs. CD8 (killer) T cells are required for clearance of primary SARS-CoV-2 infection

A: 

• Depletion of either CD4 or CD8 had moderate effects on loss of viral control. 
• However, depletion of both CD4 and CD8 T cells resulted enhanced viral replication.
• Note that Effector CD8+ T cells (cytotoxic T lymphocytes) and CD4+ T cells eradicate infected, virus-producing cells via direct killing or by secreting cytokines, such as interferon-g (IFN-γ), which enhances inflammatory functions that support viral clearance.

Q: What is the role of CD4 (helper) T cells in primary SARS-CoV-2 clearance? 

A: 

• The role of CD4 T cells is mainly to support antibody (Ab) production, because in the absence of B cells, CD4 depletion had little impact on viral control.

Q: Are T cells or Ab sufficient to control primary infection with SARS-CoV-2?

A: 

• Ab is better than T cells in controlling virus.

Q: If mRNA vax or natural SARS-CoV-2 infection establishes lung-resident CD8 T cells

A: 

• While both induced comparable circulating CD8 T cells, natural infection is much better than vax in establishing tissue-resident CD8 T cells

Q: How well does the mRNA vax or primary infection protect against VOC, and how much of that depends on CD8 T cells?

A:

• The mRNA vax or prior infection protected 100% of mice, even after CD8 T depletion at the time of challenge.
• Both mRNA vax mice and convalescent mice were completely protected from disease with original strain (WA1) and the B.1.351 virus. Even without CD8 T, all vax & convalescent mice eliminated infectious virus.
• By immunizing with varying doses of the mRNA vax, a strong correlation was found between anti-spike IgG levels, neutralizing Ab and protection against COVID-19 disease.

Figure 2. Antibody effector functions (Source: [10])

Conclusion

• While T cells were sufficient for the clearance of primary infection, they were not required for protection against reinfection or vaccine-mediated protection.^[1]
• In [1], they did not test the sufficiency of T cells in vaccine-mediated protection. 
• However, a very nice study by @Masopust_Vezys shows the promise of adding T cell antigens to vaccines:^[2]
• They show that vaccination with a human adenovirus type 5 vector expressing the SARS-CoV-2 nucleocapsid (N) protein can establish protective immunity, defined by reduced weight loss and viral load, in both Syrian hamsters and K18-hACE2 mice. 
• Challenge of vaccinated mice was associated with rapid N-specific T cell recall responses in the respiratory mucosa. 
• This study supports the rationale for including additional viral Ags in SARS-CoV-2 vaccines, even if they are not a target of neutralizing Abs, to broaden epitope coverage and immune effector mechanisms.
• In [1], they did not test the Delta variant, with its high viral load and transmission capacity, vaccines that induce mucosal immunity (TRM, IgA) may become important to better prevent infection and transmission.^[3]
• In [9], it points out that immunological protection is not provided by antibodies alone. Vaccines engage the immune system’s T-cells as well. 
• T-cells are lymphocytes that respond not just to finished proteins, as antibodies do; they also recognize protein fragments. 
• Alessandro Sette, an immunologist at the La Jolla Institute for Immunology and his colleagues have shown that T-cells preserve 93-97% of their targeting capacity when faced with a new variant.
• It [12], it shows that:
• Antibodies play an essential role in host defense against pathogens by recognizing microorganisms or infected cells. Although preventing pathogen entry is one potential mechanism of protection, antibodies can control and eradicate infections through a variety of other mechanisms (see Figure 2). 
• In addition to binding and directly neutralizing pathogens, antibodies drive the clearance of bacteria, viruses, fungi and parasites via their interaction with the innate and adaptive immune systems, leveraging a remarkable diversity of antimicrobial processes locked within our immune system. 

References

1. Adaptive immune determinants of viral clearance and protection in mouse models of SARS-CoV-2
2. Nucleocapsid Vaccine Elicits Spike-Independent SARS-CoV-2 Protective Immunity
3. In the immune arsenal, antibodies offer best long-term hope against COVID
4. Prof. Akiko Iwasaki on Twitter
5. COVID-19 vaccines: modes of immune activation and future challenges
6. Immune Responses Dictate COVID-19 outcome
7. How Vaccines Might Improve Long Covid?
8. Designing spatial and temporal control of vaccine responses (good)
9. The wonky-spiked variant Omicron looks ominous. How bad is it likely to be?
10. Lu, L., Suscovich, T., Fortune, S. et al. Beyond binding: antibody effector functions in infectious diseases. Nat Rev Immunol 18, 46–61 (2018).
11. The state of complement in COVID-19
• The complement system is an ancient, evolutionarily conserved and non- redundant component of immunity. It is classically viewed as a liver- derived and plasma- operative system constantly scanning the blood and interstitial fluids for invading pathogens and self- derived noxious antigens.