Kevin Kunzmann

See what happens when you use the words “vaccine” and “COVID-19” in the same sentence these days?

MJH Life Sciences, the parent company of 

, last night hosted the webinar COVID-19: Race for a Vaccine. Apparently, healthcare professionals can’t get enough of this topic as the webinar ran well over the hour it had been scheduled for and drew at least 2500 viewers who watched it on average for 71 minutes. And there were 422 questions from the audience afterward.

Click here to register for free, and receive a free video copy of the hour-plus expert discussion.

Here’s some of what viewers learned from presenters Walter A. Orenstein, MD, Angela Rasmussen, PhD, and Gregory A. Poland, MD, MACP, FIDSA, FRCP. (Bullet points highlighting their accomplishments are at the bottom of this article.)

There is no perfect moment to timestamp the accelerated, massive movement toward finding and distributing the first vaccine candidates for the 

There are dozens of legitimate agents making earnest progress toward clinical consideration at an unprecedented pace—in this month alone, a pair of vaccine candidates of entirely different makeup and effect reached phase 3 assessment, while another couple of candidates were agreed upon for mass distribution with countries in billion-dollar deals.

These latter vaccines have yet to even compile a full body of efficacy, safety, and tolerability data—and yet, they are the hope of national leaders.

No, this unforeseen and nonlinear process of research, application, reporting, manufacturing, and distributing of vaccines has no point on its timeline reserved for reflection and forecasting. Rather, “sooner than later” would be the most ideal time to discuss the COVID-19 vaccine race.

Rasmussen began the webinar with a quick update on the current tally of COVID-19 vaccine candidates: as per 

this week, there are more than 140 preclinical vaccines, 18 in phase 1; 12 in phase 2; 6 in phase 3; and just 1 approved for limited use—a vaccine developed for use in the Chinese military.

Among the most basic principles of vaccine development, Rasmussen said, are the exposure to antigen (weakened virus being injected into the patient), an immune response to the antigen, and immunological memory.

Historically, vaccine platforms largely came in cross-protection, toxoid, inactivated, or live attenuated forms. All 4 of these platforms and their introduction to a greater array of vaccine indications have made for “game changers in public health,” Rasmussen said.

Despite traditional vaccines being most famous for their massive reduction of smallpox and polio deaths in the few years following vaccination, they do bear shortcomings: they are difficult to mass-manufacture, slow to develop, and can result in adverse effects.

Eventually, scientists developed improved vaccine platforms:

Subunit vaccines, which uses recombinant viral proteins as antigens

Nanoparticle vaccines, which uses synthetic virus-like particles as recombinant antigens

Viral vector vaccines, which uses recombinant pseudotyped viruses as expressed antigen

Nucleic acid vaccines, which uses directly delivered nucleic acid (DNA or mRNA) encoding the antigen

Currently, investigators are assessing a half-dozen different vaccine platforms for the unique demands of SARS-CoV-2 prophylaxis: RNA/DNA vaccines, recombinant protein vaccines, vectored vaccines, inactivated vaccines, and live attenuated vaccines.

Among those to have reached phase 3 thus far have been an mRNA candidates from Moderna and the National Institutes of Health, plus a candidate from BioNTech/Pfizer and another from CureVac. The viral-vectored candidate from Oxford University/AstraZeneca is also at phase 3, as well as another candidate from Pfizer/BioNTech.

From their progression in good manufacturing practice (GMP) development, through all clinical phases of assessment, to regulatory approval and eventual distribution, administration, and developed immunity, Rasmussen anticipates the timeline may take anywhere from 6-18 months.

Poland began his session with a planted stance on the current state of debate on vaccines. “You can have your own opinions, but not your own facts,” he said. “Science is not a democracy.”

Poland stressed the scientific process—which is intentional and explicit, emphasizing repeatability, generalizability and peer review while remaining agnostic to results, and at its best when open to inquiry and willing to question dogma.

Among the highlighted hurdles of vaccine development—or, “porcupines,” he so quipped—include public concern over “cutting corners,” the allocation of vaccine and whether it is done in utilitarian or egalitarian fashion, the national levels of distribution and supply, the costs and profiteering behind it, and the overlapping “negatively synergistic threats” including COVID-19, the flu, politics, the economy, and more.

The truth, Poland said, is that despite there being 3 novel coronaviruses cross species barrier to infect humans in the last 16 years, an influenza pandemic just a decade ago, and multiple national and global tabletop exercises in place to assure preparedness, the US is continually overwhelmed by COVID-19.

“While this may have been a shock, it should not have been a surprise,” Poland said, quoting an unfortunately similar summarization of national tragedy: The 9/11 Commission Report.

Ideally, a COVID-19 vaccine would have an excellent safety profile and capable of quick mass production, room temperature stability to avoid cold chain and transportation concerns, indefinite storage, and administration that does not require highly trained providers.

Maybe, Poland said, a few of these capabilities will be met.

“We have also not well-defined vaccine efficacy targets,” Poland said. “Will it be prevention of infection? Prevention of disease? Reduction of transmission of disease?”

Based on the current standing of vaccine candidates in the development pipeline, Poland projected 4 likely scenarios:

A two-dose vaccine released in January 2021 by emergency use authorization (EUA) with a moderately high reactogenicity rate, 5% to 10% of individuals experiencing grade ≥3 serious adverse events, and an efficacy up to 60%.

A two-dose vaccine released in March 2021 by EUA, with a lower reactogenicity rate and a 70% efficacy rate.

A two-dose vaccine released in April 2021 under full licensure, with acceptable reactogenicity rate and estimated efficacy at 60% to 70%.

A one-dose vaccine released some time afterward, with a very low reactogenicity rate and efficacy up to 90%.

In all these scenarios, investigators would not be certain of long-term durability.

“My point is these are going to roll out, possibly through different mechanisms, over several months,” Poland said. “So now what? Neither the public nor providers are prepared for that. The distributor chain is not prepared for that.”

Poland also highlighted that the largest currently planned trials will have just 20,000 immunized persons. The adverse event rate for the most-assessed candidates will be just 1 per 5000.

“The fact is that part of vaccine development involves human behavior, which we are seeing play out worldwide,” Poland said.

Orenstein posted a series of questions which will likely still be unanswered at the time of a COVID-19 vaccine licensure. Among them are the duration of vaccine immunity, risk factors, the impact of the vaccine on reducing transmission, and the risk factors for if a vaccine fails or wanes in immunity.

“The key is we’re going to have to set up a monitoring system for safety and effectiveness in the long term,” he said. Such a program could borrow structure from similar systems like the FDA’s Vaccine Adverse Event Reporting System (VAERS), which operates more so as a hypothesis-generating feedback system for new vaccines.

Additionally, Orenstein suggested the idea of establishing vaccine priority—a guidance for which groups who should receive earliest consideration for available candidates.

In establishing vaccine priority groups, Orenstein stressed agencies must consider hurdles including an evolving understanding of COVID-19 epidemiology and immunology, a current absence of safety and efficacy data of COVID-19 vaccines, and the unknowns in vaccine dose timing and rate of supply.

The highest priority, Orenstein suggested, could be the healthcare and essential worker population (in order to maintain societal and treatment infrastructures), followed by the general population. These groups are comprised of approximately 122 million and 206 million Americans, respectively.

From there, both groups can be tiered by currently available vaccine supply and program planning—introducing potential SARS-CoV-2 immunity group-by-group in the US, as doses become available.

What’s currently understood in COVID-19 immune response is that most people with SARS-CoV-2 develop antibodies within 2 weeks, and that most people also mount neutralizing antibody responses.

What is not understood is the duration of immunity after SARS-CoV-2 infection, whether the neutralizing antibodies protect against viral infection, and if there are immunologic correlates of protection.

This, combined with varying levels of knowledge in vaccine development capability and platform options, as well as the effect of public health responses, poses a great challenge for the agencies held responsible for vaccine distribution.

For guidance, Orenstein shared the proposed guiding principles of vaccine priority groups, from the Advisory Committee on Immunization Practices (ACIP): safety, clinical trial inclusivity, efficient distribution, and flexibility.

When the day comes a vaccine is available, he advised physicians follow ACIP guidance, urge vaccination to high-risk population patients, report adverse outcomes to VAERS, and continue to report COVID-19 cases to local and state departments, with reference to patients’ vaccination status.

Professor and Associate Director, Emory Vaccine Center

Professor, Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine

Director, Emory-UGA Center of Excellence for Influenza Research and Surveillance (CEIRS)

Associate Research Scientist, Center for Infection and Immunity, Mailman School of Public Health, Columbia University

Mary Lowell Leary Emeritus Professor of Medicine, Infectious Diseases, Molecular Pharmacology, and Experimental Therapeutics

Articles

The webinar ran well over the hour it had been scheduled for and drew at least 2500 viewers who watched it on average for 71 minutes. And there were 422 questions from the audience afterward. 

Vaccine Experts Sound Off On Prospects for a COVID-19 Cure

Preliminary results from the phase 1/2 clinical trial of the ChAdOx1 nCoV-19 vaccine candidate from the University of Oxford showed healthy adult participants had strong antibody and T cell immune responses up to 56 days in the ongoing trial.

The trial, in which 1077 healthy adults in the UK are being assessing for the vaccine comprised of the ChAdOx1 virus for the prevention of 

, shows enough promise for further assessment and the introduction of older adults in clinical research.

 Monday morning, Oxford investigators led by Professor Andrew Pollard found the chimpanzee-based adenovirus strain that constitutes their vaccine candidate is capable of provoking a T cell response within 14 days of administration, and an antibody response within 28 days.

The trial is too preliminary to confirm whether the vaccine candidate meets requirements of an ideal SARS-CoV-2 vaccine, investigators noted—a vaccine should be effective on 1-2 administrations, work in target populations including older adults and at-risk patients, confer protection for ≥6 months, and reduce onward transmission of the virus to contacts.

But the phase 2 UK-based trial, and phase 3 trials in the UK, Brazil, and South Africa will confirm its effective protection against the virus in coming months.

The vaccine, being adenovirus viral vector, expresses the SARS-CoV-2 spike protein by using a common cold virus that infects chimpazees. It was genetically modified to code for the spike protein found in human COVID-19 patients, and intends to cause treated persons to produce the spike protein in its cells, helping the immune symptom recognize a weakened version of the SARS-CoV-2 virus.

“The immune system has two ways of finding and attacking pathogens—antibody and T cell responses," Pollard explained in a statement. "This vaccine is intended to induce both, so it can attack the virus when it’s circulating in the body, as well as attacking infected cells. We hope this means the immune system will remember the virus, so that our vaccine will protect people for an extended period. However, we need more research before we can confirm the vaccine effectively protects against SARS-CoV-2 infection, and for how long any protection lasts."

Pollard and colleagues assessed the vaccine’s effect versus control (meningococcal conjugate vaccine) in 1077 health adults aged 18-55 years old in 5 UK hospitals between April 23 and May 21 of this year. Participants had no history of COVID-19.

They were randomized to either the ChAdOx1 nCoV-19 vaccine (n = 543) or control (n = 534). Another 113 participants, split from both vaccine arms, were asked to take paracetamol before and for 24 hours after their vaccination to help reduce vaccine-associated reactions, as the vaccine candidate was administered at high doses to induce stronger responses.

Participants were further split into 4 groups: 88 people were given additional safety monitoring to form the phase 1 part of the trial, with antibody and T cell responses assessed as well; another 412 people had extra blood taken to assess for antibody and T cell responses; and 567 people had serum taken to assess for antibody response only. These 3 groups had half its participants receive the COVID-19 vaccine and half received the control vaccine.

Another group of 10 people received only the vaccine candidate, and were given an extra dose 28 days after the first to determine safety and whether a ‘booster’ improved antibody and T cell responses.

Investigators observed an acceptable safety profile, with no serious adverse events, in the vaccine candidate was found to have an acceptable safety profile and there were no serious adverse events. About 70% of vaccine-administered participants reported fatigue; another two-thirds reported headaches. Other common side events included injection site pain, muscle aches, malaise, chills, feverish sensations, and raised temperatures.

Among participants to have received the candidate, T cell responses targeting the SARS-CoV-2 spike protein were significantly increased, peaking 14 days post-vaccination (median 856 spot-forming cells per million peripheral blood mononuclear cells). Participant levels declined slightly by day 56 of the trial, to median 424 spot-forming cells per million peripheral blood mononuclear cells).

Among the 10 observed participants, T cell response did not increase with a second vaccine dose, consistent with other vaccines of this kind.

Investigators added that a small group of participants had detectable neutralizing antibodies and T cell responses against SARS-CoV-2 spike protein prior to vaccination. This was likely due to past asymptomatic infection in these adults.

The team now intends to follow up with observed participants for at least 1 year to continue to study the vaccine’s safety and induced immune response.

Study co-author professor Sarah Gilbert expressed the need for greater work to be done prior to confirming the vaccine's benefit in managing COVID-19. However, the 56-day results show promise.

“As well as continuing to test our vaccine in phase 3 trials, we need to learn more about the virus—for example, we still do not know how strong an immune response we need to provoke to effectively protect against SARS-CoV-2 infection,” Gilbert said. “If our vaccine is effective, it is a promising option as these types of vaccine can be manufactured at large scale. A successful vaccine against SARS-CoV-2 could be used to prevent infection, disease and death in the whole population, with high risk populations such as hospital workers and older adults prioritised to receive vaccination.”

The trial, in which 1077 healthy adults in the UK are being assessing for the vaccine comprised of the ChAdOx1 virus for the prevention of SARS-CoV-2, shows enough promise for further assessment.

COVID-19 Vaccine Induces Strong Immune Responses in Clinical Trial

vaccine candidate mRNA-1273 has induced immune responses in all 45 of its volunteer patients administered doses in the phase 1, dose-escalation, open-label trial.

 Tuesday evening show the vaccine candidate, encoded with a stabilized prefusion SARS-CoV-2 spike protein, induced anti-SARS-CoV-2 immune responses in all of the trial’s participants, without any trial-limiting safety concerns identified.

Investigators described the immunogenicity profile of mRNA-1273 as “rapid and robust,” particularly noting the 100-mcg dose vaccine eliciting high neutralization responses, Th1-skewed CD4 T cell responses, as well as a reactogenicity profile more favorable than the observed higher and lower doses.

The findings, reported by the mRNA-1273 Study Group, supports the advancement of a 100-mcg dose vaccine to a phase 3 trial assessment in later summer 2020, while a phase 2 trial of a pair of different doses of the potential vaccine continue among 600 healthy adults.

Moderna, along with The National Institutes of Health (NIH), announced the beginning of the phase 1 trial in mid-March. 

 3 different doses (25 mcg, 100 mcg, 250 mcg) among 45 volunteer participants in 2 doses injected intramuscularly into the upper arm approximately 28 days apart. Participants were aged 18-55 years old.

In mid-May, the US Food and Drug Administration (FDA) 

The team reported that antibody responses were greater among higher doses—as per day 29 enzyme-linked immunosorbent assay anti-S-2P antibody geometric mean titer (GMT)—after the first vaccination dose. GMTs were 40,227; 109,209; and 213,526 among the 25 mcg, 100 mcg, and 250 mcg groups, respectively.

Following the second vaccination, serum neutralizing activity was detected by 2 methods in all participants. Values were generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens.

Adverse events, including fatigue, chills, headache, myalgia, and injection site pain, occurred in a majority of patients. Systemic adverse events were more frequent following the second vaccination dose—particularly among the 250 mcg treatment arm, as 3 reported ≥1 severe adverse event.

Overall, mRNA-1273 showed signs of an immunogenic vaccine, inducing “robust binding antibody responses” to both full-length S-2P and receptor-binding domain in every participant following first vaccination.

“Seroconversion was rapid for binding antibodies, occurring within 2 weeks after the first vaccination, but pseudovirus neutralizing activity was low before the second vaccination, which supports the need for a two-dose vaccination schedule,” investigators wrote.

Though both binding and neutralizing antibody titers induced by the two-dose schedule in participants were similar to those observed by researchers in convalescent serum specimens, they stressed that COVID-19 convalescent antibody titers are variable due to patient age, disease severity, and time since disease onset.

Investigators added to what may be the first sign of an effective vaccine to SARS-CoV-2 a significant benefit of rapid manufacturing through the familiar mRNA platform.
“Product development processes that normally require years were finished in about 2 months,” they wrote. “Vaccine development was initiated after the SARS-CoV-2 genome was posted on January 10, 2020; manufacture and delivery of clinical trials material was completed within 45 days, and the first trial participants were vaccinated on March 16, 2020, just 66 days after the genomic sequence of the virus was posted.”

The discussion of what would constitute a beneficial COVID-19 vaccine for the greater population has been one of debate—yet most experts have given consideration to the variable nature of the virus, its transmission, and effects on patients. 

 stating that preventing disease or at least decreasing disease severity in at least 50% of all vaccinated persons is the bar.

 a month prior, William Schaffner, MD, professor of Preventive Medicine and Medicine at the Vanderbilt University Medical Center, discussed the greater unknown factors of a would-be COVID-19 vaccine—how long would it last? What would be its dosing regimen? Does it require a booster? Is it age-limited?

In setting a mark for overall efficacy, Schaffner was more ambitious than the FDA's guidance.

“We would hope for something that is over 80% effective,” he said. “We have to, I think, in the 21st century, have a product that is at least 80% effective. They would hope for more, of course.”

Now that Moderna's phase 3 trial dose has been finalized at 100 mcg, 

 their standing commitment to delivering approximately 500 million doses annually, and potentially up to 1 billion doses annually beginning in 2021.

New findings show the vaccine candidate mRNA-1273, encoded with a stabilized prefusion SARS-CoV-2 spike protein, induced anti-SARS-CoV-2 immune responses in all of the trial’s participants, without any trial-limiting safety concerns identified.

COVID-19 Vaccine Candidate Induces Immune Response in All Phase 1 Participants

The US Food and Drug Administration (FDA) has 

 an emergency use authorization of the antiviral drug remdesivir for the treatment of patients with coronavirus 2019 (COVID-19).

The decision comes just days after clinicians were hit with a wave of new information from an array of trials assessing the drug in patients with COVID-19. The results indicate mixed findings for benefit, but ended on an optimistic note.

The initial data released Wednesday were shared by Gilead, and were overall positive. Then the second results, from a study in Hubei, China, cast doubt on efficacy.

By the end of the day, however, remdesivir had the praise of National Institutes of Allergy and Infectious Diseases (NIAID) director Anthony Fauci, MD, who

 of another trial-overseen by NIAID-could make the antiviral a “standard of care,” although the data still need to be properly peer reviewed.

Sponsored by NIAID, the Adaptive COVID-19 Treatment Trial (ACTT) is a randomized, controlled trial evaluating remdesivir compared with placebo in 1063 patients from 68 sites (47 US and 21 countries in Europe and Asia). Participants include patients with advanced COVID-19 who exhibit evidence of lung involvement, including rattling sounds when breathing with a need for supplemental oxygen or abnormal chest X-rays, or illness requiring mechanical ventilation.

“Patients who received remdesivir had a 31% faster time to recovery than those who received placebo (p<0.001),” NIAID said in a press release. “Specifically, the median time to recovery was 11 days for patients treated with remdesivir compared with 15 days for those who received placebo. Results also suggested a survival benefit, with a mortality rate of 8.0% for the group receiving remdesivir versus 11.6% for the placebo group (p=0.059).”

 regarding the NIAID study. “[The 31% faster time to recovery versus placebo] is very important. This is a drug that can block the virus.”

 from their open-label, phase 3 SIMPLE trial of remdesivir in patients hospitalized with the virus. Investigators compared five-day and 10-day dosing regimens of the investigative antiviral drug. Similar improvement was observed in five-day dose patients (OR, 0.75; 95% CI, 0.51-1.12 at Day 14) compared to 10-day dose patients.

Half of the five-day patients reported a time to clinical improvement of 10 days, and a majority of patients in both treatment groups were discharged from the hospital in 14 days (

Participants who received remdesivir within the first 10 days of symptom onset had improved outcomes relative to those treated after 10-plus days of symptoms. Pooling data across treatment arms, 62% of patients treated within 10 days were able to be discharged from the hospital, versus just 49% of patients who were treated late.

Lead investigator Aruna Subramanian, MD, clinical professor of Medicine at Stanford University, said additional data is still needed for the ongoing, 5600-patient trial-but the current results show a better understanding of optimal remdesivir treatment duration.

shortly following the Gilead release showed adult hospitalized patients treated with the intravenous drug in Hubei, China over 10 days did not report consistently beneficial outcomes.

In assessing time to clinical improvement from baseline to 28 days post-randomization in the double-blind, placebo-controlled trial, investigators did not find an associated improvement with remdesivir (HR, 1.23; 95% CI, 0.87-1.75).

Another two-thirds (n = 102 [66%]) of remdesivir-treated patients reported adverse events, and 12% stopped treatment early, versus 64% and 5% of patients on placebo, respectively. 

Though it was considered statistically insignificant, investigators did report a faster time to clinical improvement in treated patients versus placebo (HR, 1.52; 95% CI, 0.95-2.43). Among the observed limitations to the one-month trial was the initiation of remdesivir late into COVID-19 disease course among treated patients.

Investigators suggested their assessment be replicated among larger patient populations to better inform the effect of remdesivir.

“Furthermore, strategies to enhance the antiviral potency of remdesivir (eg, higher-dose regimens, combination with other antivirals, or SARS-CoV-2 neutralising antibodies) and to mitigate immunopathological host responses contributing to COVID-19 severity (eg, inhibitors of IL-6, IL-1, or TNFÎ±) require rigorous study in patients with severe COVID-19,” they concluded.

Where does this all leave remdesivr? We asked Jason C. Gallagher, PharmD, FCCP, FIDSA, BCPS, clinical professor at Temple University College of Pharmacy and editor-in-chief of 

“Today saw an influx of data on remdesivir, much of it conflicting. A paper in 

described the results of an RCT in severely ill patients where remdesivir had no effect, though the study stopped early due to poor enrollment as COVID-19 declined in China. However, the NIAID finding in a 1000+ patient study that Remdesivir-treated patients had a 31% faster time to clinical recovery over placebo is exciting, and the trend towards a mortality benefit is promising. I want to see more of their data, particularly about outcomes in patients treated earlier vs. later in illness, and the severity of illness markers. Still, it is nice to have something positive to say about COVID-19 therapy," Gallagher said Wednesday.

The US Food and Drug Administration (FDA) has issued an emergency use authorization of the antiviral drug remdesivir for the treatment of patients with coronavirus 2019 (COVID-19).

Author | Kevin Kunzmann

Articles

Vaccine Experts Sound Off On Prospects for a COVID-19 Cure

COVID-19 Vaccine Induces Strong Immune Responses in Clinical Trial

COVID-19 Vaccine Candidate Induces Immune Response in All Phase 1 Participants

FDA Issues EUA for Remdesivir After Trio of Studies