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Once a vaccine is given approval (or more likely Emergency Use Authorization) we’ll need to prioritize who qualifies to get the vaccine first. Most likely, the vaccine will roll out with a few million doses per week- so there won’t be enough to go around at first.

The National Academy of Medicine has formed a committee to propose an equitable way to prioritize the early doses. They’ll be considering health disparities, health status, occupation, living conditions, and geographic distribution. The committee held it’s first meeting last week To attend future meetings visit here.

Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a phase 2 trial

Published:July 20, 2020DOI: https://doi.org/10.1016/S0140-6736(20)31605-6

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Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2

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).

The US government has agreed to pay Pfizer $2B for 100M doses of a potential COVID-19 vaccine.  There’s a separate contract with Sanofi/GSK for an additional 100M doses to the tune of $2.1B.  Back in May, AstraZeneca scored a $1.2B contract as an investment in the R & D and with an option to buy 100M doses. That’s basically $20/dose.

The companies expect to manufacture 100M doses by the end of 2020 and more than 1.3B doses by the end of 2021. For more information, click here.

The contracts are through a little known agency called the the Biomedical Advanced Research and Development Authority located in HHS’ Office of the Secretary. 

Side Note: Rick Bright was removed from his post as the head of BARDA back in April. He has filed an 89-page whistle-blower complaint with the Office of the Special Counsel. His complaint alleges that he was moved out of the post because of his objections to millions of dollars in contracts that have been awarded on the basis of political connections rather than scientific merit.

There are already 10 vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) in clinical trials (table), and researchers at the University of Oxford and AstraZeneca hope to have the first phase 3 data in hand this summer. 

Moderna’s mRNA-1273, which entered into clinical trials just 66 days after SARS-CoV-2 was first sequenced, showcases the potential for nucleotide-based vaccines.

Like traditional live-virus vaccines, these vaccines deliver a genetic sequence into a host cell and co-opt host machinery to express antigens of interest. However, rather than using a weakened SARS-CoV-2 to transport the code, Moderna’s vaccine uses a synthetic lipid nanoparticle to carry mRNA templates. 

The University of Oxford and AstraZeneca use a recombinant vaccine called AZD1222 to achieve a similar effect, engineering a chimpanzee adenovirus to carry DNA for the spike antigen. 

Others are focusing on more established technologies. Sanofi and GlaxoSmithKline, two of the four top vaccine producers, are working together on a protein subunit approach. Their lead vaccine candidate consists of the spike antigen itself, combined with an immunogenic adjuvant to trigger a strong immune response.

A few companies are also focusing on whole-virus approaches, in which weakened or killed SARS-CoV-2 is used to teach the immune system what to recognize.

The Lancet. 2020 6-12 June; 395(10239): 1751–1752. 10.1016/S0140-6736(20)31252-6

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.

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.

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.