Immunization Forecasts in US

Ending the pandemic crisis won’t be quick or easy. Vaccines may initially slow deaths among those with chronic conditions. But the logistical, production and public education challenges of immunizing 60% to 70% of national populations -- the level the World Health Organization says is needed to achieve herd immunity -- will be a time-consuming and troublesome process. The world will still need masks, social distancing, widespread testing and effective new therapies to keep the virus at bay, public-health specialists say.

Current Vaccine Candidates in US

Company/ Candidate	Current Clinical Trial Phase	Number of Doses Likely Needed for Full Course	Notes
AstraZenecaAZD1222 Adenovirus-vector vaccine	Phase 3	2 doses, injected	Supports advanced clinical studies, vaccine manufacturing technology transfer, process development, scaled-up manufacturing, and other development activities, to make available at least 300 million doses of a coronavirus vaccine.
Janssen (Johnson & Johnson) AD26.COV2.S Adenovirus-vector vaccine	Phase 3	1 dose, injected	Supports demonstration of large-scale manufacturing and delivery of 100 million doses of vaccine. By funding this effort, the federal government will own the 100 million doses. The government can also acquire additional doses up to a quantity sufficient to vaccinate 300 million people.
Merck/IAVI V591 Recombinant vesicular stomatitis virus (rVSV) vector vaccine	Phase 1/2	1 or 2 doses,  injected	Supports accelerated development of an rVSV-SARS-CoV2 (recombinant) COVID-19 vaccine. Based on experience with the rVSV-based Ebola vaccine, a COVID-19 vaccine using the same rVSV platform has potential to provide a rapid and robust immune response.
Moderna mRNA-1273 RNA vaccine	Phase 3	2 doses, injected	Supports manufacturing and delivering of 100 million doses of vaccine candidate. By funding this effort, the federal government will own the 100 million doses. The government can also acquire up to an additional 400 million doses.
Novavax NVX-CoV-2373 recombinant protein vaccine	Phase 3	2 doses, injected	Supports demonstration of commercial-scale manufacturing. By funding this effort, the federal government will own the 100 million doses.
Pfizer BNT162b2 RNA vaccine	Phase 3	2 doses, injected	Supports large-scale production and nationwide delivery of 100 million doses of a vaccine. By funding this effort, the federal government will own the 100 million doses. The government can also acquire up to an additional 500 million doses.
Sanofi/GlaxoSmithKline Recombinant SARS-CoV-2 Protein Antigen + AS03 Adjuvant	Phase 1/2	1 or 2 doses, injected	Supports advanced development including clinical trials and large-scale manufacturing of 100 million doses. By funding this effort, the federal government will own the 100 million doses. The government can also acquire up to an additional 500 million doses.

Best- and Worst-Case Immunization Forecasts

In a Bloomberg report, it states that:

In a best-case scenario, six vaccines are approved and rolled out shortly.  In a worst-case, only four vaccines are approved and supplies are delayed.  The two scenarios could differ by 21 months.

References

1. All-In U.S. Push for Vaccine Raises Risk Virus Lingers (Bloomberg)
2. Gilead’s coronavirus drug: why experts are cautious on its prospects (ft.com)
3. A COVID-19 vaccine: 5 things that could go wrong
4. Covid-19 vaccine delivery faces problems, warns DHL
5. Moderna COVID-19 vaccine appears to work as well in older adults in early study
• Moderna said the immune responses in those aged between ages 56 and 70, above age 70 and those 18 to 55-years-old were similar
• Moderna has never brought a vaccine to market before
6. Iceland Has Very Good News About Coronavirus Immunity
7. Inhaled Vaccines Aim to Fight Coronavirus at Its Point of Attack
8. COVID-19 antibodies last at least three months; so do symptoms for many
9. Eli Lilly Virus Antibody Trial Paused Due to Safety Concerns
10. Characterizing COVID-19 antibodies for potential treatments
11. Why and How Vaccines Work
12. How much will a Covid-19 vaccine cost?
13. Immunity from COVID-19 could last for up to 7 months, according to a new study
14. Longitudinal observation and decline of neutralizing antibody responses in the three months following SARS-CoV-2 infection in humans
15. Structural features of coronavirus SARS-CoV-2 spike protein: Targets for vaccination
16. Distributing a COVID-19 Vaccine Across the U.S. - A Look at Key Issues
17. Covid19 and the immune system — the good, the bad and the ugly 

Acquired Immune Responses Varies Substantially

When innate immunity, the initial defense against infection, is working properly — as it does in most people infected with Sars-Cov-2 who develop mild or no symptoms of disease — the second stage, adaptive immunity, kicks in after a few days.  

Warning: even mild Covid-19 infections can make people sick for months.^[14]

Figure 1.  Innate immunity vs Adaptive immunity 

Adaptive response

The nature of acquired immune responses following natural infection varies substantially among pathogens:^[11]

• Measles (1) or smallpox (2) virus
• Results in lifelong protection from the re-acquisition and re-transmission of secondary infections
• Influenza (3), respiratory syncytial virus (RSV) (4)
• Confer imperfect or transient clinical and transmission-blocking immunity either via pathogen evolution or waning immunological memory
• Dengue (5) or a vaccine (e.g., RSV (6))
• Could result in more clinically severe secondary infections due to a phenomena  known as antibody-dependent enhancement (ADE)

Table 1. Past Seasons Flu Vaccine Effectiveness Estimates (CDC Data)

VE: Vaccine Effectiveness  CI: credible Interval

Partially Effective (or Imperfect) Vaccines

The immunity conferred by such vaccines:

• May not provide complete protection against reinfection and/or disease (7)
• May be inferior to that acquired following natural infection (8)

Nevertheless, imperfect vaccines that reduce both the clinical severity and transmissibility of subsequent infections (if they do occur) can still provide population-level disease protection (7, 9, 10).

Figure. 2 Immune enhancement of human viral disease (details)

Key Questions

Obviously, a vaccine should be used only when it will benefit a patient. Benefit takes into account both the drug's ability to produce the desired result (efficacy) and the type and likelihood of adverse effects (safety).

Can an effective Covid-19 vaccine be developed?

A key question is whether protection against severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) will happen by widespread deployment of an effective vaccine or by repeated waves of infection over the next few years until ∼60 to 70% of people develop immunity. 

Because the human population is naïve to SARS-CoV-2, the consequences of repeated epidemics will be unacceptably high mortality, severe economic disruption, and major adjustments to our way of life. Therefore, the benefit of developing an effective vaccine is very high, and even greater if it can be deployed in time to prevent repeated or continuous epidemics.

Figure 3.  In antibody-dependent enhancement, sub-optimal antibodies (the blue Y-shaped structures in the graphic) bind to both viruses and Fc gamma receptors (labeled FcγRII) expressed on immune cells promoting infection of these cells. (Source: Jmarchn - Own work)

Can it be suitable for wide scale immunization?

Could the Covid-19 vaccine behave similar to the dengue vaccine?^[18]

In 2016 a partially effective vaccine for dengue fever became commercially available in the Philippines and Indonesia.  It has been approved for use by Mexico, Brazil, El Salvador, Costa Rica, Singapore, Paraguay, much of Europe, and the United States.  Based on [17], it states that:

Yesterday Sanofi Pasteur, maker of Dengvaxia, a promising dengue vaccine, announced it was changing the labeling on the vaccine to limit its use to people who have had previous exposure to dengue virus.

Pioneering dengue researchers Scott Halstead, MD, and Philip K. Russell, MD, PhD, predicted this move nearly 2 years ago. They had seen results from Dengvaxia's trials showing evidence of antibody-dependent enhancement (ADE), a dengue phenomenon that makes repeat infections more severe and can cause severe illness after vaccination in those who haven't been previously exposed to the virus.

SARS-CoV-2, like other betacoronaviruses, may have Dengue-like ADE, or antibody-dependent enhancement of disease (see Fig. 3). For those who aren’t aware, some viruses, including betacoronaviruses, have a feature called ADE. There is also something called Original Antigenic Sin, which is the observation that the body prefers to produce antibodies based on previously-encountered strains of a virus over newly- encountered ones.

In ADE, antibodies from a previous infection become non-neutralizing due to mutations in the virus’s proteins. These non-neutralizing antibodies then act as trojan horses, allowing live, active virus to be pulled into macrophages through their Fc receptor pathways, allowing the virus to infect immune cells that it would not have been able to infect before. This has been known to happen with Dengue Fever; when someone gets sick with Dengue, recovers, and then contracts a different strain, they can get very, very ill.

References

1. B. M. Laksono, R. D. de Vries, S. McQuaid, W. P. Duprex, R. L. de Swart, Measles Virus Host Invasion and Pathogenesis. Viruses 8, 210 (2016). 
2. P. D. Ellner, Smallpox: Gone but not forgotten. Infection 26, 263–269 (1998).
3. J. Dushoff, J. B. Plotkin, S. A. Levin, D. J. D. Earn, Dynamical resonance can account for seasonality of influenza epidemics. Proc. Natl. Acad. Sci. U.S.A. 101, 16915–16916 (2004).
4. V. E. Pitzer, C. Viboud, W. J. Alonso, T. Wilcox, C. J. Metcalf, C. A. Steiner, A. K. Haynes, B. T. Grenfell,Environmental drivers of the spatiotemporal dynamics of respiratory syncytial virus in the United States.PLOS Pathog. 11, e1004591 (2015).
5. N. Ferguson, R. Anderson, S. Gupta, The effect of antibody-dependent enhancement on the transmission dynamics and persistence of multiple-strain pathogens. Proc. Natl. Acad. Sci. U.S.A. 96, 790–794 (1999).
6. B. S. Graham, Rapid COVID-19 vaccine development. Science 368, 945–946 (2020).
7. S. Gandon, M. J. Mackinnon, S. Nee, A. F. Read, Imperfect vaccines and the evolution of pathogen virulence. Nature 414, 751–756 (2001). 
8. G. Anichini, C. Gandolfo, S. Fabrizi, G. B. Miceli, C. Terrosi, G. Gori Savellini, S. Prathyumnan, D. Orsi, G.Battista, M. G. Cusi, Seroprevalence to Measles Virus after Vaccination or Natural Infection in an Adult Population, in Italy. Vaccines 8, 66 (2020).
9. N. Arinaminpathy, I. K. Kim, P. Gargiullo, M. Haber, I. M. Foppa, M. Gambhir, J. Bresee, Estimating Direct and Indirect Protective Effect of Influenza Vaccination in the United States. Am. J. Epidemiol. 186, 92–100(2017). 
10. T. A. Perkins, R. C. Reiner Jr., G. España, Q. A. Ten Bosch, A. Verma, K. A. Liebman, V. A. Paz-Soldan, J. P.Elder, A. C. Morrison, S. T. Stoddard, U. Kitron, G. M. Vazquez-Prokopec, T. W. Scott, D. L. Smith, An agent-based model of dengue virus transmission shows how uncertainty about breakthrough infections influences vaccination impact projections. PLOS Comput. Biol. 15, e1006710 (2019).
11. Immune life history, vaccination, and the dynamics of SARS-CoV-2 over the next 5 years
12. Past Seasons Vaccine Effectiveness Estimates
13. Dengue Vaccine (Wikipedia)
14. Even mild Covid-19 infections can make People sick for months (Bloomberg)
15. Distinct Early Serological Signatures Track with SARS-CoV-2 Survival
16. Covid19 and the immune system — the good, the bad and the ugly 
17. Sanofi restricts dengue vaccine but downplays antibody enhancement
18. Spartacus COVID Letter

Development of Intranasal Covid-19 Vaccines in US

“The first generation of vaccines are probably going to protect a lot of people,” said Michael Diamond, an infectious disease specialist at Washington University in St. Louis. “But I think it’s the second- and third-generation vaccines — and maybe intranasal vaccines will be a key component of blocking transmission— that ultimately are going to be necessary. Otherwise, we’ll continue to have community transmission.”

Of the vaccines currently in Phase 3 trials, all are administered by injection, according to the World Health Organization (WHO).

But, based on a news from Reuters, it reported on 10/18/2020 that:

Serum Institute of India and Bharat Biotech are expected to pursue late stage clinical trials of intranasal COVID-19 vaccines in the coming months once they receive regulatory approval, Health Minister Dr. Harsh Vardhan said on Sunday.

Potential Benefits of Intranasal vaccines

Inhaled and nasal vaccine makers are counting on some of the unique features of the lungs, nose and throat, which are lined with mucosa. This tissue contains high levels of immune proteins, called IgA, that give better protection against respiratory viruses. Note that the amount of IgA produced in association with mucosal membranes is greater than all other types of antibody combined.

Antibodies secreted at the mucosal surface play an integral role in immune defense by serving to neutralize the pathogen and promote its elimination at the site of entry.

In [21], it demonstrates that:

Intranasal, but not systemic, immunization induces local IgA secretion in the bronchoalveolar space.

In Summary, intranasal vaccines may hold the below benefits:

• May offer ease of self administration
  • Don’t require needles
  • Can reduce the need for health workers to administer them
• May not need to be stored and shipped at low temperatures
• May improve vaccines’ chances of blocking Covid transmission
• The nasal route of administration mimics the natural route of infection by coronavirus and influenza and can activate both mucosal and systemic immunity
• May protect areas deeper in the lungs where the SARS-CoV-2 does the most damage
• May induce local IgA secretion in the lower respiratory tract^[21]

Considerations on Device Selection

Both liquid and dry powder formulations can be given via intranasal route. A great consideration has to be given while selecting a suitable device for nasal administration since the volume delivered is very low. A number of devices are available based on number of doses to be administered and type of dosage formulation.

Developments in US

AdCOVID (Based on a report on 10/22/2020)

Altimmune announced a preclinical evaluation of its single-dose, intranasal vaccine candidate, AdCOVID. The pre-clinical studies were conducted as part of Altimmune’s ongoing collaboration with the University of Alabama at Birmingham. These researchers stated 'AdCOVID, which promotes concomitant systemic and local mucosal immunity, represents a promising COVID-19 vaccine candidate.'

Based on the positive outcomes of the preclinical study, the Company plans to advance the vaccine candidate to a Phase 1 safety and immunogenicity study in Q4 of 2020.

CoroFlu (Based on a report on 04/02/2020)

CoroFlu, a unique intranasal vaccine against COVID-19, is under development by an international collaboration of virologists at the University of Wisconsin–Madison and the vaccine companies FluGen and Bharat Biotech. Refinement of the CoroFlu vaccine concept and testing in animal models at UW–Madison is expected to take 3-6 months. Bharat Biotech in Hyderabad, India will then begin production scale-up for safety and efficacy testing in humans. CoroFlu could be in human clinical trials by the fall of 2020.

CoroFlu builds on the backbone of FluGen’s flu vaccine candidate known as M2SR. The group will insert gene sequences from SARS-CoV-2, the novel coronavirus that causes the disease COVID-19, into M2SR so that the new vaccine will also induce immunity.

References

1. Gilead’s coronavirus drug: why experts are cautious on its prospects (ft.com)
2. A COVID-19 vaccine: 5 things that could go wrong
3. Covid-19 vaccine delivery faces problems, warns DHL
4. Moderna COVID-19 vaccine appears to work as well in older adults in early study
• Moderna said the immune responses in those aged between ages 56 and 70, above age 70 and those 18 to 55-years-old were similar
• Moderna has never brought a vaccine to market before
5. Iceland Has Very Good News About Coronavirus Immunity
6. Inhaled Vaccines Aim to Fight Coronavirus at Its Point of Attack
7. COVID-19 antibodies last at least three months; so do symptoms for many
8. Eli Lilly Virus Antibody Trial Paused Due to Safety Concerns
9. Characterizing COVID-19 antibodies for potential treatments
10. Why and How Vaccines Work
11. Serum Institute, Bharat Biotech to begin trial of intranasal COVID-19 vaccine soon: Vardhan
12. INHALED AND NASAL COVID-19 VACCINE PROGRESS
13. Advantages of Intranasal Vaccination and Considerations on Device Selection
14. Anti-COVID-19 nasal spray 'ready for use in humans'
15. Mucosal Immunity in COVID-19: A Neglected but Critical Aspect of SARS-CoV-2 Infection
16. Safety and Immunogenicity of an Intranasal SARS-CoV-2 Vaccine (BBV154) for COVID-19
17. Safety and Immunogenicity of AdCOVID in Healthy Adults (COVID-19 Vaccine Study)
18. BBV154 - A novel adenovirus vectored, intranasal vaccine for COVID-19
19. Updates on eliciting mucosal immunity for protection against SARS-CoV-2 (Tweeter thread)
20. Efficient mucosal antibody response to SARS-CoV-2 vaccination is induced in previously infected individuals
21. Intranasal priming induces local lung-resident B cell populations that secrete protective mucosal antiviral IgA

Why Is Covid More Dangerous for Older People?

Infection fatality rate of COVID-19 based on age groups (source: [6,7])

Why coronavirus is so dangerous for older people? What are the quirks of its biology that pose a unique threat to our bodies and our lives? 

How Coronavirus enters cell and replicate

Potentially Dangerous for All People

There are at least 3 reasons that Covid-19 is deadly for all people because it:

1. Is a master of deception
• Our body's cells start releasing chemicals - called interferons - once they are being hijacked by a virus and this is a warning signal to the rest of the body and the immune system.
• But the coronavirus has an "amazing capability" of switching off this chemical warning, it does it so well you don't even know you're ill.
2. Is a 'hit and run' killer
• The virus doesn't care if you die, this is a hit and run virus.
• The virus is like a dangerous driver fleeing the scene - the virus has moved on to the next victim long before we either recover or die.
• The amount of virus in our body begins to peak the day before we begin to get sick.
• But it takes at least a week before COVID-19 progresses to the point where people need hospital treatment.
3. Does peculiar and unexpected things to the body (see Fig. 2):
   
   • COVID-19 starts off as a lung disease (even there it does strange and unusual things) and can affect the whole body
   • These whole-body effects could be due to the cellular doorway the virus strolls through to infect our cells - called the ACE2 receptor (see Fig.1). It is found throughout the body including in blood vessels, the liver and kidneys, as well as the lungs.
   • Covid does more than simply kill lung cells, it corrupts them too
   • Cells have been seen fusing together into massive and malfunctioning cells - called syncytia - that seem to stick around.
   • Blood clotting also goes strangely awry in COVID-19
   • Clotting chemicals in the blood are "200%, 300%, 400% higher" than normal in some COVID-19 patients
   • Doctors sometimes were unable to get a line into a patient because it is immediately blocked with clotted blood.
   • COVID-19 can cause runaway inflammation in some patients, making the immune system go into overdrive, with damaging consequences for the rest of the body

Localized and systemic symptoms of COVID-19

Why Coronavirus is more dangerous for older people?

Different from other coronavirus, this virus is a new one, we don't think there's much prior immunity in any groups including older people.

Building an immune defense from scratch is a real problem for older people because: 

• Their immune system is slow off the mark
• Learning to fight a new infection involves a lot of trial and error from the immune system
• They produce a less diverse pool of T-cells^[9]
• So it is harder to find ones that can defend against Coronavirus.

In addition,  hospitalized older COVID-19 patients had elevated levels of pro-inflammatory markers, which including:^[9]

• Neutrophil-lymphocyte ratio, D-dimer, C-reactive peptide and certain cytokines (i.e., IL-8 and IL-27)

Based on another publication, here are the reasons why children fare better than adults:

The expression of primary target receptor for SARS-CoV-2, i.e. angiotensin converting enzyme-2 (ACE-2), decreases with age. ACE-2 has lung protective effects by limiting angiotensin-2 mediated pulmonary capillary leak and inflammation. Severe COVID-19 disease is associated with high and persistent viral loads in adults. 

Children have strong innate immune response due to trained immunity (secondary to live-vaccines and frequent viral infections), leading to probably early control of infection at the site of entry. Adult patients show suppressed adaptive immunity and dysfunctional over-active innate immune response in severe infections, which is not seen in children. These could be related to immune-senescence in elderly.

References

1. Covid: Why is coronavirus so deadly?
2. Common cold antibodies hold clues to COVID-19 behavior
3. Diverse and functional autoantibodies revealed in COVID-19 patients
4. Diverse Functional Autoantibodies in Patients with COVID-19
5. Coronavirus Deranges the Immune System in Complex and Deadly Ways
6. Pathophysiology of COVID-19: Why Children Fare Better than Adults?
7. COVID Survival Rate For Under 20s Is 99.9987%; Stanford Epidemiology Prof Study
8. Prognostic peripheral blood biomarkers at ICU admission predict COVID-19 clinical outcomes 
9. Investigating Age Differences in COVID-19 Immune Response 

How Vaccines Work and How Many Types?

Figure 1 Vaccines, PAMPs, and Adjuvants^[10]

What is Vaccine?

A vaccine 

• Is a biological preparation that provides active acquired immunity to a particular infectious disease
• Can be prophylactic or therapeutic
• Prophylactic
• Prevent or ameliorate the effects of a future infection by a natural or "wild" pathogen
• Therapeutic 
• Fight a disease that has already occurred, such as cancer
• Contains an agent that
• Stimulates the body's immune system to recognize the agent as a threat, destroy it, and to further recognize and destroy any of the microorganisms associated with that agent that it may encounter in the future. 
• Is often made from weakened or killed forms of the microbe, its toxins, or one of its surface proteins.

Virus Vaccine Types

In this article, we will focus on virus vaccines only.  Its various vaccine types include (see Figure 1):

• Live attenuated virus
• Whole killed virus
• Split virus
• Subunit vaccine
• Virus like particles
• Toxoid
• Recombinant subunit
• Conjugate
• Polysaccharide

A subunit vaccine presents an antigen to the immune system without introducing viral particles, whole or otherwise.  There are two methods of making a subunit vaccine:

1. Isolation of a specific protein from a virus and administering this by itself
2. Recombinant subunit vaccine
• Involves putting an antigen's gene from the targeted virus or bacterium into another virus (virus vector), yeast (yeast vector), as in the case of the hepatitis B vaccine[3] or attenuated bacterium (bacterial vector) to make a recombinant virus or bacteria

How Vaccines Work?

Live-attenuated (and to some degree, inactivated) vaccines have worked because they provide the two requisite signals to induce immunity:

• Antigen 
• Natural adjuvant 

But, immunization using toxoid alone induced poor immunity. #GastonRamon found that toxoid injected with ‘stuff’ (or adjuvant; see Figure 2) including tapioca, lecithin, agar, starch oil, saponin or breadcrumbs improved immunity.

Figure 2 Timeline of Adjuvant Used in Human Vaccines^[10]

New Approaches and New Types

In 1986, the first genetically engineered vaccine—the Hepatitis B surface antigen recombinant vaccine—became available

Until the last couple of decades, vaccines were developed using empirical approaches.  More recently, in parallel with increasing availability of sequencing and bioinformatics tools, there has been an increased focus on so-called “rational” vaccine design approaches.

Antibody-Dependent Immunity vs Cell-Mediated Immunity 

Antibody-Dependent Immunity

Antibodies are the focus of almost all vaccines, and currently levels of antibodies raised against the vaccine antigens are used as correlates of protection.

Cell-Mediated Vaccines 

Not all viruses are amenable to antibody-dependent immunity. Some viruses have circumvented the ability of antibodies to control them, including 

• HIV-1
• Through rapid in-host mutation and escape from antibody recognition
• Influenza virus
• Through antigenic drift to avoid previous season’s antibody recognition
• Herpes simplex virus 
• Through the expression of evasin molecules on virion surface that render antibodies useless

Fortunately, there are conserved epitopes that can be used to generate T cell immunity (or cell-mediated immunity) through vaccines. 

Neutralizing Antibody

An individual can produce hundreds or thousands of different variants of antibodies against any pathogen or foreign substance, including viruses, leading to a wide diversity of antibodies in a single person and in the human population. Some antibodies are better at blocking a virus than others. 

When an antibody effectively renders a virus unable to infect cells—knocking it out, so to speak—it is called "neutralizing."

"An ideal treatment would be a combination or 'cocktail' of different antibodies that attack the virus in different, but still effective, ways," says Christopher Barnes.^[9] "With a combination of antibodies, it's less likely that a virus can evolve to escape them."

T Cell Immunity

A key aspect of T cell immunity is that it works best if the T cells are already present at the site of entry, i.e., the mucosal surface. However, vaccines injected into muscle often fail to induce mucosa-resident memory T cells. 

A two-step vaccine strategy, prime and pull, can overcome this distribution problem by recruiting and establishing tissue-resident memory T cells in a tissue of choice (primary route of viral entry) using chemokines or chemokine-inducing agents (Iwasaki, 2016). 

T cell-based vaccines hold promise for antibody-evasive pathogens and cancer vaccines in which no surface antigens can be targeted.

References

1. Gilead’s coronavirus drug: why experts are cautious on its prospects (ft.com)
2. A COVID-19 vaccine: 5 things that could go wrong
3. Covid-19 vaccine delivery faces problems, warns DHL
4. Moderna COVID-19 vaccine appears to work as well in older adults in early study
• Moderna said the immune responses in those aged between ages 56 and 70, above age 70 and those 18 to 55-years-old were similar
• Moderna has never brought a vaccine to market before
5. Iceland Has Very Good News About Coronavirus Immunity
6. Inhaled Vaccines Aim to Fight Coronavirus at Its Point of Attack
7. COVID-19 antibodies last at least three months; so do symptoms for many
8. Eli Lilly Virus Antibody Trial Paused Due to Safety Concerns
9. Characterizing COVID-19 antibodies for potential treatments
10. Why and How Vaccines Work
    

Loch Lomond—a Sweet Scottish Song

Loch Lomond is a well-known traditional Scottish song first published in 1841.  Its sweet lyrics also hide a dark story, one that's been interpreted in a variety of ways through the centuries.

The song prominently features Loch Lomond, the largest Scottish loch, located between the council areas of West Dunbartonshire, Stirling and Argyll and Bute.

The Dark Story

The dark story goes like this:^[2]

This song is connected with the Jacobite Rebellion in Scotland and their earnest desire to return bonnie Prince Charlie as Scottish king.

And the last serious battle of the war between Scotland and England was fought on the field of Culloden.

And after the Battle of Culloden, a great number of ringleaders of the Scottish rebellions and what the Scots referred to as the young, brave laddie heroes, were taken to London for a series of show trials. Whilst they were waiting for their trials, many members of their families came from Scotland down to London. And it is quite certain that all of the people who came to the trials walked that distance. And so the wives were all there and the girlfriends and the family members and the mates and everything else. And they were all found guilty, and they were all executed in the vilest means possible. 

And so when we're talking about `you'll take the high road, and I'll take the low road,' the high road, meaning the bodies of the men that were going to be exhibited, were being taken by coach on the most important road in the country. And the ordinary poor people of Scotland, who'd seen their menfolk burn to death, all had to shuttle back by the ordinary roads that ordinary working people had to use. So that's how it was.

Video 1.  Loch Lomond - Peter Hollens (YouTube link)

Lyrics

By yon bonnie banks and by yon bonnie braes,

Where the sun shines bright on Loch Lomond,
Where me and my true love were ever wont to gae,
On the bonnie, bonnie banks o' Loch Lomond.

O ye'll tak' the high road, and I'll tak' the low road,
And I'll be in Scotland a'fore ye,
But me and my true love will never meet again,
On the bonnie, bonnie banks o' Loch Lomond.

'Twas there that we parted, in yon shady glen,
On the steep, steep side o' Ben Lomond,
Where in soft purple hue, the highland hills we view,
And the moon coming out in the gloaming.

The wee birdies sing and the wildflowers spring,
And in sunshine the waters are sleeping.
But the broken heart it kens nae second spring again,
Though the waeful may cease frae their grieving.

O ye’ll tak’ the high road and I’ll tak’ the low road,
And I’ll be in Scotland afore ye.
But me and my true love will never meet again,
On the bonnie, bonnie banks o’ Loch Lomond.

References

1. The Bonnie Banks o' Loch Lomond (Wikipedia)
2. The Dark Tale of Bonnie 'Loch Lomond' (NPR)

Long COVID: Symptoms persist for months in many survivors

Most people with Covid-19 recover within two weeks. Some, as reported in [30], with so-called Long Covid (symptoms lasting longer than three weeks), continue to experience excessive fatigue, breathlessness, headache, insomnia, muscle fatigue and pains, chest pains, persistent cough, intermittentfevers and brain fog.

It’s unclear why some people develop long Covid and others don’t, but four factors appear to increase the risk:^[37]

1. High levels of viral RNA early during an infection
   
2. The presence of certain autoantibodies 
3. The reactivation of Epstein-Barr virus 
4. Having Type 2 diabetes

The study finds about 10 per cent had symptoms for a month, with between 1.5 and 2 per cent after three months. The median age of those with Long Covid is 45, and women are more likely to be affected.

COVID-19 Symptoms Linger for Months for Many

Months after becoming ill, many COVID-19 patients still have symptoms, three studies confirm, and the more severe the initial infections, the higher the odds of persistent problems.  In [33], it describes a patient with such long COVID symptoms:

Kelly LaDue thought she was done with COVID-19 in the fall of 2020 after being tormented by the virus for a miserable couple of weeks.

"And then I started with really bad heart-racing with any exertion. It was weird," says LaDue, 54, of Ontario, N.Y. "Walking up the stairs, I'd have to sit down and rest. And I was short of breath. I had to rest after everything I did."

A year later, LaDue still feels like a wreck. She gets bad headaches and wakes up with pain all over her body on more days than not. She also experiences a sudden high-pitched whistling in her ears, bizarre phantom smells and vibrations in her legs. Her brain is so foggy most of the time that she had to quit her job as a nurse and is afraid to drive.

"These symptoms, they come and go," she says. "You think: 'It's gone.' You think: 'This is it. I'm getting better.' And then it'll just rear back up again."

The most common complaints found from 3 studies include:

• UK^[28,29]
• Post-viral fatigue
• Lasting organ damage
• Symptoms that fluctuate and move around body
• Spanish^[1]
• Shortness of breath
• Chest pain
• Palpitations
• Cough
• Physical weakness
• Psychological and cognitive disorders
• US^[2]
• Shortness of breath
• Pain with deep breaths
• Chest pain
• Heart palpitations
• Rapid heartbeat
• Confusion
• Memory loss
• Difficulty concentrating
• Dizziness
• Headache
• Impaired smell and taste
• Kidney functional decline^[35,36]

"Not caused by one thing"

So far there are more theories than clear answers for what's going on, and there is good reason to think the varied constellation of symptoms could have different causes in different people:^[33]

Maybe, in some, the virus is still hiding in the body somewhere, directly damaging nerves or other parts of the body. Maybe the chronic presence of the virus, or remnants of the virus, keeps the immune system kind of simmering at a low boil, causing the symptoms. Maybe the virus is gone but left the immune system out of whack, so it's now attacking the body. Or maybe there's another cause.

"It's still early days. But we believe that long COVID is not caused by one thing. That there are multiple diseases that are happening," says Akiko Iwasaki, a professor of immunobiology at Yale University who is studying long COVID-19.  Read [33] for more details.

References

1. Clinical and immunoserological status 12 weeks after infection with COVID-19: prospective observational study
2. Long-term COVID-19 symptoms in a large unselected population
3. The Tip of the Iceberg: Virologist David Ho (BS '74) Speaks About COVID-19
4. Even Mild Covid-19 Infections Can Make People Sick for Months
5. [WEBCAST REPLAY] COVID-19 Pandemic Update: Analysis From Neil Howe & Daryl Jones
6. Why U.S. hospitals see promise in plasma from new coronavirus patients
7. Virus May Spread Twice as Fast as Earlier Thought, Study Says
8. What Does Your Cough Say About Your Illness?
9. The COVID-19 vaccine development landscape
10. She spent 9 days in a coma and relearned how to walk. What this Covid-19 survivor wants protesters to know
11. If you’re hoping a vaccine is going to be a knight in shining armor saving the day, you may be in for a disappointment. SARSCOV2 is a highly contagious virus. A vaccine will need to induce durable high level immunity, but coronaviruses often don’t induce that kind of immunity (link)
12. Mutations map holds the key to bringing coronavirus under control
13. Virus Likely to Keep Coming Back Each Year, Say Top Chinese Scientists (Bloomberg)
• “The virus is heat sensitive, but that’s when it’s exposed to 56 degrees Celsius for 30 minutes and the weather is never going to get that hot,” said Wang Guiqiang, head of the infectious diseases department of Peking University First Hospital. “So globally, even during the summer, the chance of cases going down significantly is small.”
14. All the Covid-19 Symptoms You Didn’t Know About
15. Coronavirus: Can it affect eyesight?
16. What Troponin Tells Us About Myocardial Injury in COVID-19
• Clinicians then assess potential causes of troponin elevation, including hyperinflammation, which may respond to immunosuppressive therapy.
17. Strokes and mental state changes hint at how COVID-19 harms the brain
18. A family physician’s COVID story
19. A COVID-19 vaccine: 5 things that could go wrong
20. Studies detail conjunctivitis in kids, adults with COVID-19
21. A perspective on potential antibody-dependent enhancement of SARS-CoV-2
22. COVID-19 survivors suffer long term heart conditions
23. As evidence builds that COVID-19 can damage the heart, doctors are racing to understand it
24. Novel coronavirus survives 28 days on glass, currency, Australian researchers find
25. CDC Expands Covid Risk Warning to Include Overweight People
• Nearly 72% of American adults are overweight (25 < BMI < 30) or obese (BMI ≥ 30)
26. CDC Says Virus Can Spread Indoors in Air Beyond Six Feet
27. Covid may cause sudden, permanent hearing loss – UK study
• 16 of 121 patients admitted to hospital with Covid reported hearing problems about two months after discharge.
28. Long Covid: what we know so far
29. Living with Covid19
30. Long Covid casts a lasting shadow over workers
31. Interferon deficiency can lead to severe COVID
32. 'Brain fog' can linger with long-haul COVID-19, study says
33. New clues to the biology of long COVID are starting to emerge
34. Risk Factors for Covid-19
35. Kidney damage can result from coronavirus infection
• Kidney fibrosis, or scarring, is a serious long-term consequence that can occur virtually after any injury to the kidney and correlates with kidney function. Our work shows kidney scarring in COVID-19 patients, which provides an explanation why the virus might cause kidney functional decline as demonstrated in other studies
36. Kidney Outcomes in Long COVID
37. How Long Covid Exhausts the Body 
38. Multimodal Molecular Imaging Reveals Tissue-Based T Cell Activation and Viral RNA Persistence for Up to 2 Years Following COVID-19
39. Study details immune cells vital to success of vaccines against coronavirus
40. Study identifies shared molecular mechanisms across SARS-CoV-2 variants that allow virus to thrive despite vaccination
• Similar to treatment regimens for HIV, we believe the future approach to managing pandemics will require a drug combination cocktail.
• Here, this could include a combination of vaccines and antiviral innovations to target the virus. Specifically, combination therapy approaches to target the adaptive immune response (e.g., vaccines, antibody treatments) and another inhibiting viral innate immune antagonist proteins (e.g., Orf6 and Orf9b) or activating the innate immune response, could be the most effective. Perhaps with this approach, we may be able to get ahead of viruses before they reach pandemic levels.
41. Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis
• Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis 

Common Covid-19 Tests in US

 PCR vs Antigen 

Test	Approach	Accuracy
PCR Test	A molecular test—searches for the virus’s genetic material in a nasal swab or saliva sample, and it is often processed in a highly complex laboratory	Tests run in lab: highly accurate Tests run in boxlike analyzers: less accurate
Antigen Test	Search the sample for viral proteins instead of the virus’s genetic code, are gradually becoming more widespread in the U.S.	Considered less precise than PCR tests Considered most accurate when used in the early-symptoms stage

Cost / Turnaround Time

Test	Cost	Turnaround Time
PCR Test	If you have symptoms or have had contact with someone infected, typically free Otherwise, could be $60 to $300 (if not covered by insurance)	Offered at a drive-through location, a doctor’s office, a pharmacy such as CVS or Walgreens or a lab Time: Boxlike analyzers: 15 to 45 mins Offsite lab: > 2 days
Antigen Test	If you have symptoms or have had contact with someone infected, typically free Otherwise, could be $25 to $100 (if not covered by insurance)	Offered at doctor’s offices, nursing homes and other congregate settings where groups of people need testing fast. Time: Typically 15 mins

Which test hurts the least?

“If it doesn’t hurt, they’re not doing it right,” said Frank Peacock, associate chair of the department of emergency medicine at Baylor College of Medicine, of the deeper nasal swabs.

Collection Method	Ranking of Pain Level
Spitting into a container	Least
Cheek swabs	Moderate
Nasal swabs	Moderate
Deeper nose swabs	Most

Caution with Results

A test represents only a snapshot of a moment in time. Depending on the test you get and how the sample is collected, you may receive a false negative or false positive result due to:

• Sample collection or test errors
• Test collected too early 
• Some people may seek a test before a detectable amount of virus has built up, which could produce a negative result even if they are infected. 
• Test collected too late
• Tests can pick up the genetic material of the virus and produce a positive result when patients are no longer infectious.

References

1. Covid-19 Tests: Answers on Cost, Accuracy and Turnaround Time
2. Saliva viral load is a dynamic unifying correlate of COVID-19 severity and mortality
• A new research at Yale found that saliva viral load to be a better predictor of disease than nasopharyngeal viral load.
3. Chinese cities using anal swabs to screen COVID-19 infections
• Stool tests may be more effective than respiratory tests in identifying COVID-19 infections in children and infants since they carry a higher viral load in their stool than adults, researchers at the Chinese University of Hong Kong (CUHK) had said in a paper published last year.