Building an Investigative Army in 100 Days


By: Mindy Miner, PhD, HVTN Core, Seattle, WA, USA

WHY/HOW WAS THE CoVPN DEVELOPED?

The birth of a network

The first week of March 2020 brought several changes to the Seattle area. HVTN workers were ordered by Fred Hutch to work remotely. Conferences, such as the large annual HIV meeting CROI, went virtual. And infectious disease physicians and scientists everywhere started focusing on what they could do about severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) and the disease it causes, COVID-19. HVTN Principal Investigator Larry Corey’s weekly calendar shifted from meetings about HIV antigens and monoclonal antibodies to how to combat the SARS-CoV-2 epidemic in Seattle and how to develop what he knew was the burgeoning scientific infrastructure and initiative on developing vaccines to the new pathogen. By then, National Institute of Allergy and Infectious Diseases (NIAID) Director Tony Fauci was on television every day as part of the White House Coronavirus Task Force and his conversations  with Corey were reminiscent of those 20 years ago when the HVTN began. Mainly, that we (the nation) needed a seamless infrastructure to get these vaccines tested as soon as humanely possible. John Mascola, director of the National Institutes of Health (NIH) Vaccine Research Center (VRC), and Fauci became Corey’s most frequent cell phone and text contacts on the development of an NIH/Biomedical Advanced Research and Development Authority (BARDA) infrastructure, and conversations on how to build a nationwide investigative organization to handle this task were initiated. Confidentiality agreements to allow access to information were signed and the task began in earnest.

When a global catastrophe like the COVID-19 pandemic hit, the HVTN’s infrastructure and experience became priceless. Two decades of developing vaccine and monoclonal antibody clinical trial protocols. Two decades of building relationships with physician-scientists, pharmacists, and clinic staff. Two decades of community engagement programs collaborating with local advocacy groups to reach people most burdened by disease. Two decades of immunology lab assays perfected and Federal Drug Administration (FDA)-approved. Two decades of statistical expertise analyzing large datasets.

“This expertise in HIV needs to and can be leveraged,” Corey said. “Our faculty site investigators are all  interested in and affected by this epidemic. There is universal support for doing this.“

The first HVTN COVID-related protocol, which opened May 13, 2020, was HVTN 405/HPTN 1901: characterizing SARS-CoV-2-specific immunity in convalescent individuals (convalescent means someone who recovered from disease). The time of concept sheet (initial protocol idea) to trial opening (screening participants) was 1 month. The median for HVTN trials has been well over a year. Before the US government’s (USG) Operation Warp Speed was even created, before the Network had even been given the official gracing of a new name, the Network was operating at ‘warp speed.’ It’s a tribute to the staff that they could and did embrace the mantra of quality and speed to this task. This does not mean corners were cut; only that this trial was the priority for everybody – HVTN, HPTN, Division of AIDS, etc. There was no longer a delineation between weekdays and weekends. The HVTN saw early on how the pandemic would cripple the economy and society, much like a World War, and therefore all hands were on deck to end it as quickly as possible. 

The new COVID-19 Prevention Network (CoVPN) was born, with Corey and Kathy Neuzil (from the Infectious Diseases Clinical Research Consortium and University of Maryland) as head of the operations center and HPTN’s Mike Cohen and Emory University’s David Stephens leading the monoclonal antibody program. The NIAID oversight team included Emily Erbelding, Carl Dieffenbach, Mary Marovich, and Mascola. “This is not business as usual” became the new mantra around the remote office. “We’re building the plane as we fly it” was another favorite analogy at the time. Trial names would not begin with ‘HVTN,’ but now have ‘CoVPN’ numbers.

Finding an efficacious vaccine wasn’t the only problem. The logistics of manufacturing, packaging, and distributing a vaccine to billions of people is, in a word, complicated. [Read a recent viewpoint in Science Magazine by Corey et al to go into depth.] That is just for one vaccine. Now multiply that by four or five different companies and things get crazy. It was apparent to CoVPN leadership that these efficacy trials, involving as many as 30,000 people each, would need to be harmonized – something pharmaceutical companies haven’t historically worried about. But in order to make sense of results, sample collection, lab assays and statistical analyses would need to be consistent across all trials. The CoVPN is making sure that happens.

Engaging the nation

The HVTN/CoVPN Community Engagement Team, led by Michele Andrasik, faced a formidable challenge on participant recruitment. The group couldn’t just repurpose the HVTN’s longstanding HIV materials. A simple ‘find/replace’ for ‘HIV/SARS-CoV-2’ in an informed consent form would not be adequate. Not only are the viruses, and the respective diseases they cause, extremely different, but so are the target audiences for educational materials. Historically, when participants volunteered for an HVTN Phase 1 study, they often commented their participation stemmed from a passion for stopping a disease that affected them or their communities personally. But now, with a global pandemic that has infected 40 million people worldwide and killed more than 1 million in under a year, people who may have never thought twice about infectious disease or public health have become the target demographic. Nursing home residents, grocery store clerks, and bus drivers are examples of populations at risk for COVID-19.

There the challenge laid: a new disease, a new demographic(s). The team consulted with expert panels for recommendations on engaging priority communities, mainly African American/Black, Latinx, Native/Indigenous and older adult populations. The team developed a suite of materials in record time. A website was built (www.PreventCOVID.org). Informational videos were produced. Flyers, posters and brochures received Institutional Review Board approval and hit the streets. In addition, the CoVPN received federal funding to develop and produce a series of public service announcements (PSAs) in both English and Spanish aimed at recruiting Americans for the vaccine trials.

The CoVPN developed a Volunteer Screening Registry, led by HVTN Executive Director Jim Kublin, that allows people interested in volunteering for a trial to sign-up. Within a week of going live on July 7, 2020, more than 91,000 people had signed up. As of late October, the number rose to over 407,000, with now more than 515,000. Many of the CoVPN clinical research sites have used the registry to prioritize those populations that have been disproportionately impacted by the national epidemic. Participants in the registry have also contributed to a public service announcement narrated by Harrison Ford, and the registry will continue to provide participants for all efficacy trials regardless of vaccine or monoclonal antibody developer.

Expanding the reach

The Network (HVTN-now-CoVPN) increased its number of US clinical trials sites from 62 in June 2020 to 151 in September: more than doubling its national footprint in a mere few months (Figure 1). This new cadre of sites included for the first time Veterans Administration Facilities, Historically Black Medical Colleges, and the Indian Health Service. The Site Operations Team, led by Niles Eaton, worked tirelessly to not only onboard new sites in the US and internationally, but also prepare longstanding HVTN sites for the era of COVID. Site preparation visits were restructured to be virtual. Running clinical trials during a pandemic is logistically complex. Sites needed personal protective equipment for safe clinic reopening, educational materials for volunteer recruitment, nasal swabs and PCR machines for testing. At least 29 of these sites, according to Eaton, will most likely employ one or more temporary locations, such as a mobile clinic, trailer, or tent, to reach individuals in remote locations. 

Figure 1. Rapid site expansion both within the US and internationally.
Figure 1. Rapid site expansion both within the US and internationally.

WHAT PRODUCTS ARE BEING TESTED, AND WHICH COMPANIES ARE INVOLVED?

The CoVPN is currently involved in five COVID-19 vaccine efficacy trials, which are scheduled to open approximately one per month for the remainder of the year (Figure 2). All these vaccines have advantages and disadvantages with regard to speed of manufacturing, scalability, type of immune response, and target population.

Figure 2. Expected course of Phase 3 clinical trials.
Figure 2. Expected course of Phase 3 clinical trials.

Moderna

The first trial to open, the COVE Study, used a two-dose nucleic acid-based approach developed by the company Moderna (modernatx.com/cove-study). This vaccine uses the relatively novel platform of messenger RNA (mRNA) that encodes for the main surface protein of SARS-CoV-2, the spike protein. Advantages of this vaccine include speed of production, ability to deliver multiple antigens at the same time, and durable antibody responses. Although many Phase 1 studies using mRNA vaccines have shown promise, none have reached licensure. The SARS-CoV-2 viral genome sequence was published January 10, 2020 and the COVE Study opened 6 1/2 months later on July 27, 2020. This speed is unparalleled in history. It usually takes decades between deciphering what pathogen causes disease to a vaccine efficacy trial.

AstraZeneca

The second CoVPN trial to open was a vaccine developed by Oxford University and subsequently sold to the company AstraZeneca. The vaccine regimen, also two-dose, uses a viral vector from a chimpanzee adenovirus (Ad) that does not cause disease in humans. This vaccine, like the Moderna vaccine, encodes for the SARS-CoV-2 spike protein. The trial began in August 2020 and was subsequently put on hold due to adverse events. The hold was lifted in late September in Europe/Brazil/South Africa, where a parallel trial is being conducted, and the FDA approved restart in the US on October 23, 2020.

Janssen

The third trial to begin was another adenovirus vector vaccine, this time using human Ad26 as the backbone delivering the spike protein antigen and developed by Janssen (part of Johnson & Johnson). One aspect of the ENSEMBLE Trial is that the regimen includes one dose, as opposed to two doses for each of the other vaccine trials. A one-dose regimen is advantageous logistically, especially if hundreds of millions of people need to be vaccinated. The Ad26 backbone was recently shown to be safe and stimulate a robust immune response against Ebola and is the platform used in the HIV efficacy trials HVTN 705 (Imbokodo) & HVTN 706 (Mosaico). This trial was also temporarily put on safety pause for approximately 10 days in October in response to adverse events. It has since resumed.

Novavax & Sanofi Pasteur

Two more trials are in the process of being developed, one by the company Novavax and the other by Sanofi Pasteur, scheduled to open in late 2020. Both vaccines will be two-dose and use traditional recombinant protein technology to deliver the spike protein. Protein vaccines are widely used globally and given to people of all ages, something important to consider if COVID vaccination plans in the future include children.

One important point is that these companies would, under normal circumstances, never produce millions of doses of a vaccine before FDA approval and licensure, much less concurrent with the efficacy trial. The reason they are doing so in this case is because the USG has agreed to purchase those doses, regardless of whether they show efficacy, resulting in minimal risk to the company. This is why the field has made such strides so quickly.

HOW MANY PEOPLE ARE NEEDED FOR EACH STUDY?

Approximately 30,000 participants are needed for each vaccine trial in order to have what statisticians call “power” to determine whether the vaccine provides any benefit or efficacy against COVID-19 disease. Based on current epidemiological projections and what is known about disease progression, the CoVPN can assume that for each 30,000-person trial, it will take approximately 24 weeks from trial opening to accrue enough “endpoints” to determine efficacy. An endpoint is COVID-19 disease.

WHAT IS THE STATUS OF EACH STUDY?

Table 1 lists the CoVPN studies and their status as of October 2020. In addition to the five Phase 3 vaccine trials mentioned above, the CoVPN is involved in several monoclonal antibody studies as well as observational studies to learn about disease prevalence and immune responses.

Table 1. CoVPN pipeline of studies and status

 

Study Type CoVPN trial number Short description Company Status
  3001 mRNA-1273 Phase 3, the COVE study Moderna Enrollment complete, in follow-up
  3002 AZD1222 (ChAdOx1 nCoV-19) Phase 3 AstraZeneca Open and enrolling
Vaccine 3003 Ad26 Phase 3, the Ensemble study Janssen Open and enrolling
  3004 Protein Phase 3 Novavax In Development
  3005 Protein Phase 3 Sanofi Pasteur In Development
  3501 α-SARS-CoV-2 antibody Phase 3, the BLAZE-2 study Eli Lily Open and enrolling
Monoclonal Antibody 3502 α-SARS-CoV-2 antibody cocktail Phase 3, the REGN-COV study Regeneron Open and enrolling
  3503 α-SARS-CoV-2 antibody Phase 2/3 Vir/GSK In development
Observational 5001 Acute immune responses to SARS-CoV-2 infection N/A Open and enrolling
  5002 SARS-CoV-2 prevalence N/A In development
Operational 6001 Screening registry for participation in CoVPN trials N/A Open and enrolling

In summary

The HVTN/CoVPN is in the middle of the most important health crisis of the last century. Not since the 1918 influenza pandemic have we seen such rapid morbidity and mortality from an infectious disease. Unlike the 1918 flu, when approximately 1/3 of the world’s population was infected and ~50 million people died, the COVID-19 pandemic is occurring at a time of unparalleled biomedical advances and information technology. Humanity’s ability to join together and overcome this virus will be something never forgotten.


Dr. Mindy Miner is the Science Writer/Editor of the HVTN. Dr. Larry Corey and Dr. Jim Kublin, HVTN Principal Investigator and HVTN Executive Director, respectively, contributed to this article.