Issue No. 66: Developing, Manufacturing, and Deploying The Vaccines to Keep Us Safe From COVID-19

Social distancing, masks and therapeutics help, but to snuff out the current COVID-19 pandemic and protect against another one, the world needs a vaccine – that is, a preventive medicine that mobilizes the immune system to fight off the SARS-CoV-2 virus that causes the disease.

According to a World Health Organization tracking report, nearly 200 COVID vaccine candidates are in development, and 44 of them are in clinical trials, with 14 in Phase 2 and 10 in final Phase 3 evaluation, which involves assessing safety and effectiveness among thousands of people.

On Nov. 9, Pfizer and BioNTech, the U.S. firm’s German partner, announced that their Phase 3 vaccine candidate “has demonstrated evidence of efficacy against COVID-19…based on the first interim efficacy analysis” conducted by an external, independent data monitoring committee. The vaccine was “found to be more than 90% effective in preventing COVID-19” in a study enrolling 43,588 participants. The companies announced 94 confirmed cases of infection but said that the clinical trial will continue “to final analysis at 164 confirmed cases in order to collect further data.” In a later update, the companies said the final analysis of 170 cases found the vaccine to be 95% effective and had no serious side effects.

Pfizer and BioNTech on Nov. 20 submitted a request to the U.S. Food & Drug Administration (FDA) for an Emergency Use Authorization (EUA), which would “potentially enable use” of the vaccine candidate, dubbed BNT 162b2, “in high-risk populations in the U.S. by the middle to end of December.”

Meanwhile, on Nov. 16, Moderna, a Cambridge, Mass.-based biotech, announced that its own vaccine candidate registered 94.5% effectiveness in early trial data. Moderna, too, is expected to request an EUA.

Normally, it can take more than a decade to develop a vaccine. It took 20 years for polio. In this case, however, vaccines went into development in January, when Chinese scientists published the 30,000-letter genetic code for SARS-CoV-2. At the time, only 41 cases and one death had been identified in Wuhan. The code allowed researchers all over the world to make their own synthetic versions of the virus. Moderna took its vaccine to clinical trials in 66 days, believed to be a record.

While some of the Phase 3 trials have been interrupted to evaluate safety concerns and take the time to ensure that the trials can proceed, at least one of the U.S. or European vaccines will almost certainly be authorized under an EUA by December or early 2021. Tony Fauci, director of NIAID at the National Institutes of Health, told CBS in early October that scientists would know by December whether a vaccine will be safe and effective – and his prediction appears correct. Ensuring the safety and efficacy of a vaccine is a serious undertaking – necessary for consumers, providers, and public health leaders to build confidence in this important preventive measure and help drive uptake.

Such a vaccine could then be available widely in the U.S. by April. But achieving the objective of vaccinating enough people to create global immunity is daunting. An article in September by Barry R. Bloom of the Harvard T.H. Chan School of Public Health and colleagues in the New England Journal of Medicine made these calculations:

Data from antibody testing suggest that about 90% of people are susceptible to Covid-19. Accepting that 60 to 70% of the population would have to be immune, either as a result of natural infection or vaccination, to achieve community protection (also known as herd immunity), about 200 million Americans and 5.6 billion people worldwide would need to be immune in order to end the pandemic. The possibility that it may take years to achieve the vaccination coverage necessary for everyone to be protected gives rise to difficult questions about priority groups and domestic and global access.

All of the vaccines in Phase 3 trials are being tested in two doses, taken three to four weeks apart – a process that stretches the time to full global immunization even further.

Speeding and Accepting

The Trump Administration has tried to move the vaccine development and production process along with a program called Operation Warp Speed, with a goal “to produce and deliver 300 million doses of safe and effective vaccines with initial doses available by January 2021.” The program was funded with up to $10 billion, and money has quickly been made available for development, manufacturing, and distribution, including $1.5 billion to Johnson & Johnson, $2 billion to Moderna and $1.6 billion to Novavax. Pfizer chose to risk only its own money on vaccine research. The U.S. government committed $1.95 billion for delivery of up to 100 million doses of the vaccine developed by Pfizer and BioNTech upon EUA approval. The agreement also lets the U.S. acquire up to 500 million additional doses.

The often-confusing White House efforts to address COVID-19 more generally and the unfortunate political atmosphere around those efforts may affect acceptance of a vaccine by the public. In September testimony, government health officials told Congress that they would not speed approval for political reasons, and around the same time, nine pharmaceutical companies issued a joint pledge that they would “stand with science” and not put out a vaccine that had not been until it had been thoroughly vetted for safety and efficacy. Nevertheless, on Oct. 19, California Gov. Gavin Newsom said he would set up an independent state board to “independently review and monitor any vaccine trials to guarantee safety.” Newsom said, “Of course, we don’t take anyone’s word for it.”

The FDA has final say on approval, and it receives recommendations from the independent Vaccines and Related Biological Advisory Committee, made up mainly of practitioners and academics.

Americans, nevertheless, have not exactly embraced the idea of being vaccinated for COVID. A recent Stat/Harris Poll survey found that only 54% of Americans said they would get vaccinated as soon as they can. The problem is not cost. The vaccine will be free. But some 79% said they worry about a vaccine’s safety if it is approved too quickly. Still, this hesitation may vanish as people see their neighbors vaccinated and as the benefits of personal immunization become more obvious.

Sharp Decline in Non-COVID Vaccine Use, Except for Flu

While vaccines against the novel coronavirus were being developed at a record pace, vaccines with other life-saving uses, developed years ago, were sitting on shelves waiting to be used. The COVID-19 epidemic itself, including challenges in assessing vaccines in traditional locations during the pandemic shutdown and building vaccine confidence, are raising risks that other vaccine-preventable diseases could spread.

A WHO survey in June found that 85% of the 61 countries polled had experienced declines in vaccinations. The disruptions, to both outreach and inoculation services, were worst in Africa and the Americas. When asked why, 48% of respondents said patients worried about getting COVID-19 when they go to a doctor’s office, clinic or hospital to be vaccinated; 33% cited lockdowns or limited public transport. Other problems include lack of personal protective equipment, or PPE, for health workers – and the low availability of those workers, busy fighting the coronavirus.

On July 15, the WHO reported “an alarming decline in the number of children receiving life-saving vaccines around the world…. This is the first time in 28 years that the world could see a reduction in DTP3 [diphtheria, tetanus and pertussis] coverage – the marker for immunization coverage within and across countries.”

More recent data, though sparse, show a slight rebound. Vaccinations will probably return to previous levels as the pandemic moderates – though that may not happen for another six months or longer. Research by the Bill and Melinda Gates Foundation, released in September, found that while global vaccination rates for pediatric measles, mumps and rubella fell from 84% to 70% because of COVID, they are forecast to rebound within a year.

The situation in the U.S. during the early COVID period was particularly challenging. Between the week of Feb. 16 and the week of April 5, administration of measles, mumps and rubella shots dropped 50%; diphtheria and whooping cough shots by 42%; HPV [human papilloma virus] vaccines, by 73%. A separate study by the Centers for Disease Control (CDC) found that measles shots for children aged 2 to 18 dropped 90% over the period.

Even before COVID-19, however, Americans were displaying an increasing lack of confidence in vaccinations. The proportion of respondents saying it is “very important” for children to be vaccinated dropped from 81% to 72% between 2008 and 2018, according to a study by Research America and the American Society for Microbiology. A separate Gallup survey confirmed the decline and found that 16% of parents with children under 18 believe that “vaccines are more dangerous than the diseases they prevent.”

Such fears were behind the lower vaccination rates that existed prior to the epidemic. For example, only 69% of California children aged 18 months to four years had had all of their shots as of 2018, and only 45% of adults received flu shots for the 2017-18 season, according to the CDC. Among adults over 65, only 69% had been vaccinated for influenza over the past 12 months and just 64% had ever had a pneumococcal vaccine while 34% had had a shingles vaccine. Overall, the flu vaccination rate for Americans over six months during the 2019-20 season was just 52%, including just 44% of those with chronic conditions, the CDC reports.

But although COVID depressed other vaccinations, it has inspired more Americans to receive flu shots, at least so far – in part because of fears of a double-whammy with the coronavirus. From Aug. 7 to Oct. 2, some 23.5 million got shots, compared with 12.6 million during the same period last year.

Developing a Vaccine

“The traditional vaccine timeline is 15 to 20 years. That would not be acceptable here,” says Mark Feinberg, president and CEO of the International AIDS Vaccine Initiative, quoted by the STAT news service. “When you hear predictions about it taking at best a year or a year and a half to have a vaccine available,…there’s no way to come close to those timelines unless we take new approaches.”

And those new approaches are, in fact, being taken. Researchers are working simultaneously on steps that would normally be taken sequentially, such as testing prospective vaccines on mice at the same time they are tested on humans. Vaccines have a long history of safety, and, whatever means are used to speed up the approval process, it’s certain that regulators are conscious of not increasing risks.

A big reason that the vaccine can be approved relatively quickly is the speed with which Chinese scientists published code that allowed researchers all over the world to make their own synthetic versions of the virus. Also, while no one knew that the next pandemic would come from a coronavirus, vaccine researchers had hedged their bets by focusing on such pathogens, which they had seen before with SARS (2002) and MERS (2012). “The speed with which we have [produced vaccine candidates] builds very much on the investment in understanding how to develop vaccines for other coronaviruses,” said Richard Hatchett, CEO of the Coalition for Epidemic Preparedness Innovations (CEPI), quoted by Laura Spinney in The Guardian.

Also helping push the development process have been multiple sources of government and non-profit funding. For example, CEPI, an Oslo-based non-profit, has provided initial funding to Moderna, Curevac, Inovio, Novavax, Themis, the Institut Pasteur in Paris, and the Universities of Oxford, Pittsburgh, Hong Kong, and Queensland to develop COVID-19 vaccines. CEPI has raised $690 million of the $2 billion it says it needs, with funding from such governments as the U.K., Germany, and Canada. Meanwhile, Inovio, a small Pennsylvania biotech that has also received funding from the Gates Foundation, became the second firm to start Phase 1 testing on a vaccine and is now in Phase 2.

Another advantage has been the eagerness of global drug companies and research institutions to cooperate. The small German firm, BioNTech, as noted above, has partnered with Pfizer (whose Prevnar 13 vaccine targets pneumococcal disease) while Oxford University is working with the British-Swedish firm AstraZeneca and Moderna with the National Institute of Allergy and Infectious Diseases (NIAID). EpiVax, a Providence, R.I.-based immunology company has a partnership with the GAIA Vaccine Foundation, a U.K. non-profit, to crowd-source funds for a project that “is using advanced computational tools to accelerate a COVID-19 vaccine candidate (EPV-CoV19) for healthcare workers.”

GlaxoSmithKline (GSK), based in London, struck a deal with China’s Xiamen Innovax Biotech to develop a vaccine and, more broadly, is making its adjuvant technology, which boosts immune response, “available to scientists and organizations working on promising COVID-19 vaccine candidates.”

Novavax, a Maryland company, previously developed vaccines for MERS and SARS which, according to a press release, “demonstrated strong immunogenicity and 100% protection against virus challenge in preclinical testing.” The Sars-CoV-12 virus shares 80% to 90% of its genetic material with the virus that causes SARS, and Novavax, working with an NIH grant, is repurposing its previous coronavirus vaccines to work against COVID-19, and its RNA-based vaccine is now in Phase 3 trials.

The Sars-CoV-12 virus is made up of RNA (ribonucleic acid) inside a protein capsule, whose distinctive spikes lock onto ACE2 receptors on human cells. The RNA breaks into the cell, makes copies of itself, and the upper and lower airways Traditionally, vaccines have introduced part or all of the pathogen (in a live but weakened form, or else rendered inactive) into the human body, whose immune system recognizes the danger and starts producing disease-fighting antibodies to fight it. The antibodies continue to work for months, years, or a lifetime, depending on the vaccine.

Edward Jenner founded the science of modern vaccinology when, in 1796, he injected a 13-year-old boy with vaccina virus, or cowpox and demonstrated immunity to smallpox. A century later, Louis Pasteur deployed live weakened cholera vaccine and inactivated anthrax vaccine. In the early 1950s, Jonas Salk grew large quantities of polio virus on cultures of monkey cells, then killed the virus with formaldehyde, creating a vaccine that would save millions of lives.

No Live Virus Necessary

Today, instead of killing an actual live virus, some pharmaceutical companies are instead using new technologies. Novavax says it “uses recombinant protein technology to imitate the structure of a virus to provide protection without the risk of infection or disease.” For COVID-10, according to Spinney, “This involves extracting the genetic code for the protein spike on the surface of Sars-Co-V-2, which is the part of the virus most likely to provide an immune reaction in humans, and pasting it into the genome of a bacterium or yeast – forcing those microorganisms to churn out large quantities of the protein.”

Moderna and CureVac are building their vaccines not from proteins but from genetic instructions themselves. Pfizer and BioNTech are using technology that they developed working together in recent years on influenza vaccines, synthetically producing RNA. “When a person is injected with the RNA, their own muscle cells would turn into vaccine ‘factories,’ creating proteins that stimulate the immune response,” says a Pfizer description.

Innovation is being spurred by an industry that is researching both competitively and collectively. “Across the whole industry we are seeing lots of coordination,” said Michael Breen, associate director of infectious diseases at GlobalData, speaking on a FiercePharma panel of experts. “This is actually a proven method for success in vaccines for pathogens related to outbreaks," he added, referring to Merck’s Ebola vaccine Ervebo, which started at a research institute in Canada and was originally licensed by NewLink Genetics, based in Iowa. The Ebola outbreak, however, began in 2014, and Ervebo was approved only in December 2019. The world can’t wait that long for a COVID-19 vaccine.

Manufacturing the Vaccine

A vaccine not only must be researched, developed and approved; it has also to be manufactured in enough doses for billions of people around the world. Hatchett, the CEO of CEPI, said in an interview with STAT in early February that he believed there would be several vaccine candidates developed quickly, but he added:

And then for each candidate, you need to ask yourself the question: How do you produce that? How do you get that candidate to a point where regulators are comfortable with it being used widely and how are you going to get to that point with production at a scale that is meaningful in the context of a disease that is going to infect the whole of society?

The good news is that manufacturing is being ramped up well before vaccines are approved. CEPI announced Oct. 21 that it had reserved manufacturing capacity for one billion doses of vaccine globally, signing agreements with Biofabri of Spain and GC Pharma of South Korea.

Bill Gates, told Trevor Noah on “The Daily Show” April 2 that his foundation will work with seven makers of a potential vaccines to build factories now, before approval. Said Gates: “Our early money can accelerate things. Even though we’ll end up picking at most two of them, we’re going to fund factories for all seven, just so that we don’t waste time in serially saying which vaccine works and then building the factory.” He could lose billions on the choices that don’t pan out. “A few billion,” he said, “is worth it.”

The Trump Administration’s Warp Speed program has invested billions of dollars for this purpose. As an example, back in June, the Department of Health and Human Services announced $204 million in funds for Corning to expand the domestic manufacturing capacity to produce approximately 164 million glass vials per year for vaccines. And on Oct. 13, HHS and the Pentagon announced a $31 million agreement with Cytiva, a supplier to pharmaceutical companies, to expand manufacturing capacity for products that are essential in producing COVID-19 vaccines, such as cell culture media. The Defense Department and HHS also announced a $138 million contract with ApiJect for more than 100 million prefilled syringes for distribution by the end of this year, as well as the development of manufacturing capacity for the ultimate production goal of over 500 million prefilled syringes by 2021.

Pfizer is already manufacturing millions of doses of its vaccine and expects to have as many as 50 million doses globally ready by year-end, according to a company official. The UK’s Daily Mail on Oct. 18  published video showing a manufacturing plant in Puurs, Belgium, with thousands of doses of the vaccine coming off the production line. According to FiercePharma, Pfizer earlier “tagged sites in Kalamazoo [Mich.], Andover, Massachusetts, and St. Louis for its U.S. COVID-19 production.” 

The company’s complicated logistical operation was described Oct. 21 by the Wall Street Journal. For example:

To keep the vaccines safe in transit and to move them fast, Pfizer designed a new reusable container that can keep the vaccine at ultracold temperatures for up to 10 days and hold between 1,000 and 5,000 doses. The suitcase-sized boxes, which are packed with dry ice and tracked by GPS, will enable Pfizer to avoid the larger, temperature-controlling containers used in transportation, giving it more flexibility to ship the vaccines faster since planes and trucks won’t have to wait for the standard refrigerated metal boxes.
 
Many of the emerging vaccine candidates, including Pfizer’s, will be easier to manufacture in large quantities than traditional vaccines, which are typically developed from viruses grown on primary cells such as chicken eggs. And researchers are innovating with mass-production firmly in mind. For example, in announcing a vaccine candidate that will be delivered through a finger-sized patch with tiny needles, University of Pittsburgh scientists stated:

The system also is highly scalable. The protein pieces are manufactured by a "cell factory" -- layers upon layers of cultured cells engineered to express the SARS-CoV-2 spike protein -- that can be stacked further to multiply yield. Purifying the protein also can be done at industrial scale. Mass-producing the microneedle array involves spinning down the protein-sugar mixture into a mold using a centrifuge. Once manufactured, the vaccine can sit at room temperature until it's needed, eliminating the need for refrigeration during transport or storage.

"For most vaccines, you don't need to address scalability to begin with," said Pittsburgh researcher Andrea Gambotto. "But when you try to develop a vaccine quickly against a pandemic that's the first requirement."

Getting the Vaccine to the People: The Role of Pharmacies

The final step in the process is getting vaccines to the people who need them, which, in this case, is practically everyone in the world except perhaps those who already have immunity, having survived the illness.

How will vaccines be distributed if physician office visits have been supplanted by telemedicine and hospitals are still overwhelmed with COVID-19 cases? Even if these obstacles are gone by the time a vaccine is available, the obvious answer is pharmacies.

There are 67,000 pharmacies in the U.S., staffed by more than 300,000 licensed pharmacists, nearly all of whom have continued to work through the pandemic. Nine out of ten Americans live within five miles of a pharmacy, and “in rural and underserved communities and in areas experiencing physician shortages, pharmacists may be the only healthcare provider that is immediately accessible to patients,” says a briefing paper on the COVID-19 crisis signed by the CEOs of a dozen associations representing pharmacists.

In September, HHS authorized “state-licensed pharmacists to order and administer, and state-licensed or registered pharmacy interns acting under the supervision of the qualified pharmacist to administer, COVID-19 vaccinations to persons ages 3 or older.”

That HHS had to issue the order highlights the restrictions that many states place on pharmacists’ immunizing Americans against other diseases.

As Wayne Winegarden of the Pacific Research Institute noted in a Forbes article, “All accredited Doctor of Pharmacy programs require to obtain an immunization certification, and all pharmacists that administer vaccines are trained on the CDC’s national immunization standards and recommendations.” But while every state permits pharmacists to administer flu vaccines, state regulations vary for other vaccines, and in many states current rules would either prevent pharmacists from administering COVID-19 vaccines or delay immunizing Americans by requiring prescriptions from physicians.

A LawAtlas study found that, as of 2016, just ten states allow pharmacists to administer vaccines independently; another five states do not specifically grant them authority without prescriptions but do not expressly prohibit the practice either. The remaining states allow immunization only according to a protocol approved by a physician or an institution.

The value of immunizations by pharmacists, who, unlike most physicians, can vaccinate people on a weekend, in the evening, and without an appointment, is undeniable. A 2018 study published in the journal Vaccine by researchers at the Johns Hopkins School of Public Health is especially relevant today. The study used a computer simulation model to find the effect of adding pharmacies as locations to dispense flu vaccinations. During a mild epidemic, this approach would have…

averted up to 17.1 million symptomatic cases, prevented up to 104,761 deaths and saved $1 billion in direct medical costs, $49.3 billion in productivity losses and up to $50.3 billion in societal costs (direct medical and indirect costs combined). In a more severe epidemic, adding pharmacies averted up to 23.7 million symptomatic cases, prevented up to 210,228 deaths and saved $2.8 billion in direct medical costs, $97.1 billion in productivity losses and $99.8 billion in overall costs.

In their briefing paper, the pharmacists’ organizations urge that, in adding to vaccinating Americans, pharmacists should be allowed to initiate treatment. Already in Idaho, pharmacists are authorized to prescribe products to treat strep and flu, and “Florida recently passed a law permitting pharmacists to test and treat for strep, flu and other non-chronic ailments.”

Certainly, physicians and hospitals will play a major role in the immunization effort, but they can’t do it alone. Now is the time – in the months before a vaccine is approved and manufactured – for all states to review their laws and make the necessary changes to expand access. As a statement by the American Disease Prevention Coalition put it:

Every state must ensure that all pharmacists can administer FDA-approved or ACIP [Advisory Committee on Immunization Practices]-recommended vaccines. States should make these changes now so that pharmacists can administer a COVID-19 vaccine as soon as it reaches the market. The lives of millions of Americans may depend on it.

The approach that officials are taking with COVID contrasts with the barriers against other vaccinations. In a good illustration of an innovative approach that could be adopted for many diseases, HHS and DoD last month announced agreements with CVS and Walgreens to vaccinate residents of the nation’s long-term care facilities. Pharmacy staff will administer the immunizations on-site at no out-of-pocket cost to residents.

Still, even with COVID vaccines, there are obstacles. All but three states have registries to keep track of vaccinated residents. Registries help physicians and pharmacists remind people to get a second dose for vaccines that require them – was well as preventing people from getting vaccinated for the same disease too many times. But the registry system needs federal guidance for uniformity and easy access by professionals.

Who Pays for Vaccines?

The federal government has announced that the COVID-19 vaccines that it has purchased during the pandemic will be free for all Americans.

The CDC on Oct. 13 made an announcement about priorities, saying that the Advisory Committee on Immunization Practices was “considering four groups to possibly recommend COVID-19 vaccination for if supply is limited.” Those groups are healthcare personnel, workers in “essential and critical industries,” people who are at high risk “due to underlying medical conditions,” and people over 65.

Seniors suffer the highest fatality rates from COVID-19. As an article in Health Affairs by Richard Hughes IV of the consulting firm Avalere and two co-authors noted, Congress in the 1980s required that “influenza, pneumococcal, and hepatitis B vaccines be covered under Medicare Part B with zero cost sharing.” Other immunizations fall under Medicare Part D, for which there is an out-of-pocket component. But the recently enacted Coronavirus Aid, Relief, and Economic Security (CARES) Act added coverage of a COVID-19 vaccine without cost sharing.

For non-Medicare beneficiaries, the Affordable Care Act (2010), passed on the heels of the 2009 H1N1 influenza outbreak “requires that all vaccines recommended by [ACIP] be covered without cost sharing by non-grandfathered commercial health insurance plans and Medicaid expansion programs.”
 
“If you have private health insurance in this country, you will not have to worry about any out-of-pocket costs when it comes to COVID-19 vaccines,” said Dr. A. Mark Fendrick, director of the University of Michigan’s Center for Value-Based Insurance Design (V-BID) in Ann Arbor, quoted by Healthline.

The federal government, however, needs to tie up some loose ends. It has to set an adequate, flat reimbursement fee for physicians and pharmacists to cover the cost of administering the vaccine and counseling patients. While these professionals are conscientious and public-spirited, they need the incentive of compensation, especially to encourage those in low-income neighborhoods and rural areas to get vaccinated. In addition, the government should clarify that no Americans should be faced with cost-sharing for having their vaccine shots administered.

Access to vaccines is the final step in the process of protecting Americans – and the world – from COVID-19, and, unless we’re flexible and innovative, it could be the most difficult.