Will Humble Disease Control, Vaccination, Wills Blog

The SARS CoV-2 Vaccines: What are the Approaches?

Developing a vaccine is a complicated process, but the fundamental idea behind a vaccine is straight-forward. Vaccines train the immune system to recognize and combat pathogens (viruses or bacteria). A vaccine basically simulates the pathogen (in our case the SARS CoV-2 virus) by introducing an antigen specific to the target virus.

That triggers an immune response and the body forms antibodies and killer T cells to fight what it believes is the invading virus (and remembers them for the future). If the person is later exposed to the virus, the immune system will recognize the antigens immediately and attack aggressively before the pathogen can spread and cause sickness.

The key to vaccines is injecting the antigens into the body without causing the person to get sick. Scientists have developed several ways of doing this, and each approach makes for a different type of vaccine.

Recombinant Vaccines

A recombinant vaccine is a vaccine produced via DNA technology. This involves inserting the DNA encoding an antigen (such as a bacterial surface protein) that stimulates an immune response expressing the antigen in cells.

The University of Oxford and AstraZeneca vaccine uses a recombinant vaccine. A chimpanzee adenovirus carries a DNA code the for the SARS CoV-2 spike antigen into cells. The body then mounts an immune response to the SARS antigen. This vaccine is in Phase III trials with about 50,000 participants (but they’re starting with 10,000).

m-RNA Vaccines

This is a new approach to making a vaccine. Moderna and Pfizer are using this new approach.  They deliver nano-particle mRNA genetic sequence into host cells which tells the cell to replicate the SARS CoV-2 virus protein coat, triggering the immune response.

Both these manufacturers are just beginning their Phase III trials. The Moderna’s Phase III trial will have 30,000 participants in the US. Arizona is a participating trial location. Pfizer’s will also be 30,000 persons but will be in 3 different countries.

Inactivated Vaccines

For these vaccines, the specific virus or bacteria are killed with heat or chemicals, and the dead cells are introduced into the body. Even though the pathogen is dead, the immune system can still learn from its antigens how to fight live versions of it in the future. 

A few companies are also focusing on whole-virus weakened or killed SARS-CoV-2 virus. The Sinovac vaccine uses this approach. It’s in Phase III trials with 9,000 healthcare workers in Brazil.

Subunit/conjugate Vaccines

For some diseases like SARS CoV-2, scientists can isolate a specific protein or carbohydrate from the pathogen that can train the immune system to react without provoking sickness. 

Sanofi and GlaxoSmithKline are working together on a vaccine that uses this protein subunit approach. Their lead vaccine candidate consists of the spike antigen combined with an adjuvant.

Live Attenuated Vaccines

For these types of vaccines, a weaker, asymptomatic form of the virus or bacteria is introduced into the body. Because it’s weakened, the pathogen won’t cause sickness, but the immune system will still learn to recognize its antigens and know to fight in the future.

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What are Vaccines and How are they Tested & Approved?

Vaccines basically make a person’s immune system think that it’s been exposed to a harmful virus. The trick is to get the body to make antibodies and T  cells to fight to fight what it perceives as a threat. Those antibodies and T cells then stand at the ready to fight the real thing in case a person is exposed to the real virus or bacteria.

Once researchers think they’ve found a way to safely trick the body into an immune response you’re ready to start testing it to make sure it works and is safe.

There are a couple dozen candidate vaccines in various stages of testing around the world. Each country has their own way of deciding whether a vaccine is safe and effective.

So, how does the testing system in the US work and how will we know if a vaccine is effective? It really comes down to using the scientific method to develop and test the vaccine using clinical trials and carefully doing a statistical analysis to see whether the vaccine is safe and works (called safety and efficacy).

Phase 0 

The first step for most vaccines is to conduct animal studies to see whether a proposed vaccine elicits an immune response, usually in primates. The animals are vaccinated and then researchers check for an immune response. If an immune response happens (antibodies are produced) then they may decide to go to a Phase I human trial.

The SARS CoV-2 vaccine candidates probably skipped this step because it’s optional in emergencies.

Phase I

The first test in humans is a Phase I Trial. During Phase I, small groups of healthy people receive the proposed vaccine (less than 100 people). Some people will get the actual vaccine, and some will get a placebo (e.g. adjuvant or salt water).

The people don’t know whether they’re getting the real thing or not. The vaccine group will usually have a few different doses to measure how that effects the response.

Researchers do periodic blood draws and look to see whether people in each group make antibodies (and usually T cells too). They also look at health outcomes and side effects. They do statistical analyses to estimate how well the vaccine produces an immune response and whether and what kinds of side effects it has. This is done by comparing what happened in each group (vaccine vs. the placebo group).

If Phase I shows that the vaccine elicited a statistically significant immune response and the side effects weren’t bad, then it can proceed to a Phase II trial. It’s not ethical to proceed if the side effects are bad or if it doesn’t work.

There are at least 10 vaccine trials that have completed Phase I.

Phase II

The SARS CoV-2 Phase II trials use the same approach as Phase I- with a vaccine and a placebo group, varying doses, and careful tracking of whether antibodies (and T cells) are made.  They also look for side effects in both groups.

The big difference is that Phase II will have more volunteers (usually in the hundreds of people). Just like Phase I, they select healthy volunteers. Phase II will also usually include a wider variety of doses and dose scheduling (timing).

If the Phase II statistics show that the vaccine produced an immune response (at least in some doses and scheduling categories) and if there weren’t bad side effects, they may proceed to Phase III.

This article shows the various trials underway or completed in this category, including the Astrazenica (UK) and Moderna (US) vaccine candidates.

Phase III

Phase III testing is the “real deal” and takes a lot longer than Phase I and II. Phase III trials are done with a much larger number of people (several thousand). The participants are more diverse. Both the challenge and placebo groups have a broader range of ages. They also test a wider variety of doses and administration schedules.

Phase III is the real-world test for the SARS CoV-2 vaccines. Both groups participate in the trial and then go out in the world and live their lives. They continue to come in from time to time for a blood draw to look for the immune response and to check for side effects. In Phase III the researchers also look to see what happens to each group over time.

One thing they look for is how many people in each group gets the disease (in this case COVID-19). This is called examining the “clinical efficacy” (including infection rates and severity).

By comparing results in each group (both by looking at who contracts the disease and the side effects), the researchers can tell whether the vaccine is safe and effective, and if it is, what doses and scheduling are likely to work the best (or if some doses are unsafe).

If Phase III goes well, the company usually asks that the vaccine be approved by the FDA’s Center for Biologics Evaluation and Research.

They listen to the FDA’s Vaccines and Related Biological Products Advisory Committee. That Committee evaluates the safety and efficacy data and the quality of the trials and then makes a recommendation to the FDA Commissioner who ultimately decides whether to approve the vaccine or not.

In the case of the SARS CoV-2 vaccines, the companies will be most likely be asking for Emergency Use Authorization rather than formal approval which would let them begin using the vaccine even though it hasn’t gone through the normal FDA approval process.

Phase IV

This is an ongoing process that all vaccines go through. In Phase IV real world effectiveness is evaluated and there’s a continuing search for uncommon but serious side effects. This monitoring is done by the manufacturer and the CDC FDA vaccine safety system. 

Volunteer for a Vaccine Clinical Trial

The COVID-19 Prevention Network and the NIH are responsible for the oversight of the Phase 3 efficacy trials for COVID-19 vaccines in the US. You can volunteer to participate in a Trial by visiting the COVID-19 Prevention Network.

I volunteered for a clinical trial and it only took about 15 minutes. Arizona has been selected for one of the Moderna vaccine test sites because the prevalence of COVID-19 is so high here.

Will Humble Disease Control, Vaccination, Wills Blog

The ABC’s of the SARS CoV-2 Vaccines

Some of the most talented researchers in the world have been working on developing a vaccine for the SARS CoV-2 virus that causes COVID-19. More than 28 candidate vaccines are under development around the world. They’re in various stages of testing. Several use new technologies, others more established approaches. Many are showing very promising results.

Central governments around the world are largely financing these efforts. Normally, vaccine manufacturers pay for the research and make decisions about the trials and going to market based on their potential return on investment.

In this case, central governments (including the US) are financing and buying vaccines in advance so production can begin during the trials. They’re making guarantees to buy even if the vaccine doesn’t end up working or is unsafe. This is speeding up the process by months, even years.

Each day this week I’ll be blogging about the main vaccine candidates, the methods they’re using, the way the trials work (including how to volunteer for a clinical vaccine trial), and an overview of the testing protocol and describe the approval process.

Will Humble Disease Control, Wills Blog

AzPHA and the School Nurses Organization of Arizona Issue Joint Recommendations for the Safe Return of In-person School

Today the AzPHA and the School Nurses Organization of Arizona issued joint recommendations as benchmarks for the safe return of in-person teacher-led classroom instruction as outlined in Executive Order 51. View our Open Letter here and the text below:

July 30, 2020

Governor Douglas A. Ducey

Office of the Governor

1700 West Washington

Phoenix, Arizona 85007

Dr. Cara Christ

Director, Arizona Department of Health Services

150 N. 18th Avenue

Phoenix, Arizona, 85007

Dear Governor Ducey and Dr. Christ,

On behalf of the Arizona Public Health Association and School Nurse Organization of Arizona, we strongly recommend the postponement of in-person public education in Arizona until specific evidence-based measures are in place.

While many school districts have developed quality mitigation plans to lower the risk of spread, community transmission is currently too high to adequately protect children and staff. Testing capacity is inadequate, sample turn-around times are insufficient, contact tracers are receiving tardy data, public health laws are inadequate and unenforced, and testing and infection control in care homes needs improvement. 

All the above issues are fueling community spread and need to be improved before schools open for in-person instruction this fall. There are two categories of criteria we ask you to use when making this decision:

  • The quality of school district mitigation plans and their ability to execute those plans with fidelity; and

  • Evidence-based criteria that measure community transmission.

Specifically, we recommend that you consider the following community spread measures as benchmarks for the safe return of in-person teacher-led classroom instruction as outlined in Executive Order 51:

  • A consistent 30-day reduction in the number of new COVID-19 cases in the county as measured by a 7-day moving average;

  • A county percent positive rate of less than 5% for 21 days as measured by a 7-day moving average;

  • 90% of samples returned by analytic laboratories within 72 hours of specimen collection with a transparent metric on the ADHS Dashboard; and

  • Community hospitals open for elective procedures.

When a community meets all these criteria, the district could be free to set a date for in-person instruction.  If community transmission rebounds and the above criteria are no longer met, then districts should suspend in-person instruction.

Having measurable criteria in place to make that happen can build additional community motivation to achieve and maintain the important mitigation measures that reduce transmission of the virus.

Thank you for your consideration of our recommendation.

Sincerely,

Aimee Sitzler, MSW

President,

Arizona Public Health Association

Board of Directors School Nurses Organization of Arizona

Will Humble Disease Control, Wills Blog

Hospital News from the Field

There’s finally some good news from the field this week. Providers are reporting that they see a plateauing – if not an actual downturn  in key hospital-specific metrics.  However, despite these improvements the pressure on hospitals remains significant and variability in patient need and human resource availability continues. To date the AZ Surge Line has supported over 1800 patient transfers.

Providers are increasingly recognizing the importance of using the rapid antigen test as a long-term strategy for optimal transfer decision-making, patient cohorting, and support for under-resourced behavioral health and community service organizations.

St. Luke’s Hospital Alternate Care Site Update

You’ll recall that a couple of months ago there was a high-profile press conference out at the old closed St Luke’s hospital. The governor and health director talked at length about how that would become an acute care surge hospital in the event of a “worst case scenario”. The plans have changed and now St. Luke’s is would become a step-down non-acute care site (if needed). Over $8M in state dollars have been used to prepare the facility. 

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Journal Articles of the Week

Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial

This is the study that you likely heard about early in the week with the promising results from the Astra Zenica Phase II vaccine trial in the UK.  Promising results indeed! Not only did the vaccine tested form antibodies at several doses, it also generated cell mediated immunity (called killer T cells). 

Contact Tracing during Coronavirus Disease Outbreak, South Korea, 2020

In this new study published in CDC’s Emerging Infectious Disease South Korean researchers found that kids younger than 10 transmit to others much less often than adults do, but the risk is not zero. And those between the ages of 10 and 19 can spread the virus at least as well as adults do.

Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report

Among hospitalized patients with Covid-19, treatment with dexamethasone resulted in lower 28-day mortality than usual care, according to the level of respiratory support the patients were receiving, indicating a possible correlation between efficacy and the stage of infection.  Read the article.

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Open Letter from AzPHA & University of Arizona Faculty and Staff Regarding COVID-19 Response Recommendations

The AzPHA and many faculty and staff from the University of Arizona sent this open letter to the Governor and ADHS Director this week. It provides our evidence-based recommendations for improving the COVID-response in Arizona.

July 28, 2020

Governor Douglas A. Ducey

Office of the Governor

1700 West Washington

Phoenix, Arizona 85007

Dr. Cara Christ

Director, Arizona Department of Health Services

150 N. 18th Avenue

Phoenix, Arizona, 85007

Dear Governor Ducey and Dr. Christ,

Arizona’s COVID-19 cases have grown exponentially, increasing from 400 cases a day in May to 5000 daily cases in July. The use of evidence-based, proven strategies could curb the spread of the virus, allowing businesses and schools to re-open safely and preventing further harm.

On behalf of the researchers and professors at the University of Arizona’s Mel and Enid Zuckerman College of Public Health and the Arizona Public Health Association, we respectfully request an enhanced government response to Arizona’s COVID-19 pandemic that would include the following: 

Address testing shortages and delays

Inadequate test availability and delays in delivering test results make it harder to identify and treat those currently infected.  Currently, test results may not be received for 7-14 days, making it more difficult to isolate infected individuals and track the people they contacted. Test shortages could be addressed, and we could be kept safer by:

  • Committing to achieving laboratory turn-around times of less than 72 hours for 90% of samples and placing this metric on the ADHS COVID dashboard.

  • Dramatically improving testing within assisted living and skilled nursing facilities.

  • Increasing use of antigen testing, which is more rapid and has a higher negative predictive value than the existing PCR and antibody tests in use in our state.

  • Expediting testing for individuals with symptoms and expanding testing for asymptomatic individuals, who may be unaware they are spreading the disease.

  • Allowing for testing without a doctor’s order.

  • Processing tests more efficiently using sample pooling techniques currently under development.

  • Expanding test availability to all communities, mobilizing walk-through testing in communities with limited transportation and renewing targeted “blitz” testing in high prevalence areas.

Expand use of masks

To keep us safe, robust government action is needed to promote mask wearing. Mask wearing also should be required and enforceable statewide, since the failure of individuals to act responsibly ultimately affects us all. Messaging about mask wearing should include education on its proper use (e.g. masks must cover both the nose and mouth, avoid contact with the outside of the mask, and techniques to avoid self-inoculation). Masks should also be made available to those who can least afford it, including those experiencing homelessness.

Develop compliance and enforcement system for CDC mitigation measures

Implementation and compliance with CDC mitigation measures in retail stores, restaurants, bars, and other public places is inconsistent.  We urge you to develop a workable compliance and enforcement system that includes a hotline for community complaints to ensure compliance with CDC mitigation measures. Arizona has a successful model in the Smoke Free Arizona Act.  We urge you to build and implement a similar model to improve mitigation measure compliance.

Curb the spread among those most at risk

This moment makes clear that the health of every person in our state is intertwined. We can’t afford to leave anyone out of efforts to stop the spread of disease.  This includes people in institutional settings that care for older adults or persons with disabilities who are at risk due to their proximity. It also includes those close-quarter settings where farm workers, prisoners, and meat packers work or reside.

Enhance community-level data collection and response

Strategies should be developed to prevent, rapidly identify and swiftly address outbreaks in local communities. For example, to better identify where the virus is spreading, randomized testing could be conducted locally so that communities needing added resources could be identified. Such data and related information should be transparently shared statewide, allowing resources to be better targeted to communities or populations in need. To ensure effective partnership in COVID-19 mitigation efforts with tribes in Arizona, tribal sovereignty must be recognized to protect and promote data rights and interests.

Strategies should also be developed to address emerging the needs of various local communities. For example, community-based teams should be deployed to help local businesses better assess and modify their work environment to minimize infection risk. 

To effectively educate the public about COVID-19 and how we can each play a role is stopping its spread, it is important to engage trusted, local partners using linguistically-appropriate messages and materials.  Culturally-responsive partners such as tribal community health representatives and promotoras can connect with those who are hard to reach.

Increase treatment capacity

Since intensive care units are nearly full currently, elective surgeries should be scaled back to provide hospitals an opportunity to safely serve the community, protect health care personnel, and ensure adequate supply of hospital beds, personal protective equipment (PPE). Additional action is also needed to address continued shortages of PPE and health care workers.

Help people isolate or quarantine

While each of us bears responsibility for stopping the spread of the virus, it is important to recognize that many who become sick may face challenges isolating. This includes those who care for children or elders; individuals lacking or residing in inadequate housing where self-isolation is impossible; those who feel a need to continue to work due to their job or financial situation; and those experiencing mental illness.  Strategies should be developed to ensure everyone has a safe, supportive environment for quarantine, isolation, and recovery. 

Better leverage technology

Technology could play a role in allowing individuals to receive and submit health information. However, limited access to technology and privacy concerns and misperceptions may limit its use.  Existing platforms, such as AZCOVIDTXT, could be expanded and efforts could be made to address privacy concerns and misconceptions. Public-private partnerships could also expand use of technology in addressing public information and information exchange.

Use comprehensive metrics for decisions regarding re-opening our education

Decisions to open K-12 schools and Universities should be data-driven measured, scaled and responsive approaches to resumption of in-person activities. Clear phases should be guided by metrics that include epidemiological indicators of transmission, and public health, testing and medical capacities. Educational institutions should further demonstrate their ability to monitor and respond to adherence to mitigation strategies and changes in internal transmission and broader community impacts of their re-opening. Mitigation strategies should be clear, public and follow public health guidelines. Community health workers could be trained to periodically assess institutional adherence. 

Now is the time for government to act to stop further spread of COVID-19. We’re at a critical juncture, demanding robust government action based on what we know works.

Sincerely,

Aimee Sitzler, MSW

President,

Arizona Public Health Association

University of Arizona Faculty and Staff:

Kacey C. Ernst, PhD, MPH

Katherine Ellingson, PhD

Kristen Pogreba-Brown PhD, MPH

Leslie V. Farland, ScD

Elizabeth T. Jacobs, PhD, MS

Sydney Pettygrove, PhD

Purnima Madhivanan, MBBS, MPH, PhD

Megan Jehn, PhD, MHS

Pamela Garcia, PhD, MPH

Bonnie LaFleur, PhD, MPH

Paloma I. Beamer, PhD

Joe K. Gerald, MD, PhD

Mark Nichter, PhD, MPH

Saskia Popescu, PhD, MPH, MA

Erika Austhof, MPH

Lindsay Kohler, PhD, MPH

Jill de Zapien, BA

Aminata Kilungo, MPH, PhD

Joshua Hunsaker, BS

Collin Catalfamo, MPH

Kelly M. Heslin, MPH, CHES

Stephanie Carroll, DrPH, MPH

Yann Klimentidis, PhD

Maia Ingram, MPH

Felina Cordova-Marks DrPH, MPH

Elizabeth Hall-Lipsy, JD, MPH

Cecilia Rosales, MD, MS

Kelly A. Reynolds, PhD, MS

Will Humble Disease Control, Wills Blog

In-Person School Start Criteria in the Works

At the urging of Superintendent Hoffman, the governor signed Executive Order #51 last Thursday outlining a process to make better decisions about whether and how to set in-person instruction start dates. For the last several days, we, the Superintendent, teachers, and others have been advocating for a more evidence-based process to set school start dates. Our advocacy worked!

Prior to last Thursday, the governor had been setting proposed in-person instruction dates- but there had been no objective evidence-based criteria associated with those dates.

Last Thursday’s Order also requires face coverings for students over 5 years old when in-person services or instruction begins. There are exceptions for some students and during playground time when outside distancing is happening.

The Order requires the ADHS to develop public health benchmarks that school districts may use to inform their in-person instruction dates. The deadline for developing the criteria is August 7.

While the Order itself doesn’t mention how or whether the county health departments will be involved in setting the criteria, Superintendent Hoffman mentioned the importance of involving the county health departments- which is super-important as they are the public health retailers in Arizona.

While we still need to see what the criteria will be- this is certainly a victory for evidence-based public health policy and the students, parents and educators of Arizona.

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