Safe and effective vaccines represent the most effective way to restore the health and economic security disrupted by the Covid-19 pandemic. To help achieve that goal, the U.S. government launched Operation Warp Speed in May to accelerate development and manufacturing of several Covid-19 vaccines, with a goal of having 300 million doses available to the U.S. population by January 2021.

Operation Warp Speed is expediting vaccine development primarily by moving clinical trials forward without pauses between phases, and by scaling up manufacturing capacity before knowing if a candidate works. Three candidates are currently in Phase 3 pivotal trials, with initial results expected as early as this fall. At least three other candidates are expected to enter advanced clinical development soon.

At the same time, physicians, scientists, and the public are increasingly concerned that the speed with which Covid-19 vaccines are being developed, as well as the unprecedented political pressure being exerted on the FDA, as occurred surrounding controversial emergency use authorizations (EUA) for Covid-19 treatments, may pose undue risks to the vaccine development and evaluation process — and thus to the population — and that an unproven vaccine might similarly receive an emergency use authorization.

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A recent survey reported that about 35% of Americans might decline to get an FDA-approved Covid-19 vaccine. Only 22% of respondents in another survey said the U.S. should prioritize making vaccine available before it has fully been tested, while 64% favored full testing, even if that delays access. Another survey found that a majority — Democratic and Republican — worry that vaccine approval is being driven by politics rather than science.

Covid-19 vaccines can help stop the pandemic only if people trust them and want to be vaccinated. To earn and keep the trust of the American people, our government needs to ensure three key needs are met before launching any immunization campaign.

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Ensure transparency and confidence in FDA decisions

The FDA has said that Covid-19 vaccines would be approved using its usual high standards of safety and effectiveness, based on controlled studies, and only if the vaccines reduce cases of Covid-19 by at least 50%. Each Phase 3 vaccine trial plans to enroll at least 30,000 individuals and will randomly allocate volunteers to receive either the investigational vaccine or a placebo. Most, if not all, of the Covid-19 vaccines will require two doses, several weeks apart.

The more cases of Covid-19 that occur in the community, and the more effective a vaccine is, the sooner we may have definitive results on vaccine effectiveness.

It is possible that in a public health emergency, the FDA could make an unapproved vaccine available under an emergency use authorization before it meets the standards required for approval. Given the toll of the Covid-19 pandemic, early access to a vaccine that has not yet met all requirements for full approval, but that has been found to be safe and effective in Phase 3 clinical trials and whose manufacturing and quality has been found satisfactory by the FDA, may be beneficial in saving lives. However, the FDA has not clarified what evidence would be required to support such an EUA, which by law requires only that a product “may” be effective and have what the FDA judges to be a favorable benefit-to-risk ratio.

In its guidance on Covid-19 vaccine development, the FDA appears to suggest that Phase 3 trials should be completed with findings of safety and effectiveness before any vaccines are authorized for emergency use. FDA Commissioner Stephen Hahn, however, recently said that emergency use authorization could be issued before Phase 3 trials are completed.

Because vaccines are given to healthy people, making the tolerance for even rare serious adverse effects very low, and the need for public confidence in immunization, we believe that access to a Covid-19 vaccine under an EUA should occur only after clear and substantial evidence of safety and effectiveness has emerged from Phase 3 trials. We also believe that any use of a Covid-19 vaccine under an EUA should be targeted to individuals at highest risk of infection or its complications, who are clearly informed they are being offered an as-yet-unapproved product, and who consent to receiving it.

The earliest vaccine candidates are based on technologies not previously used in approved vaccines or manufactured at large scale, limiting experience in safety and quality. In addition, no vaccine is 100% effective and there are biologically plausible but unproven concerns that a partially effective Covid-19 vaccine could result in worsened disease if breakthrough infections occur in vaccinated individuals.

For all these reasons, there must be clear communication to the public and recipients about what is known and what is not yet known about each vaccine’s safety and effectiveness and, for any unapproved product, a clear explanation of why it is not yet approved.

The FDA has indicated that it will seek input from its Vaccines and Related Biological Products Advisory Committee before any Covid-19 vaccine approval or emergency use authorization, “to ensure the public has a clear understanding of the evidence supporting vaccine safety and efficacy.” This welcome step will help ensure that key data and deliberations are public and that input from nongovernmental experts and the public is considered.

Politicians must immediately refrain from pressuring the FDA regarding the timing or outcome of its decisions. It is essential that the public be able to trust that independent experts at the FDA have assessed all the evidence and made decisions based on the facts. Similarly, vaccine developers should not be unduly pressured concerning the pace of development and thresholds for regulatory submission. Finally, communication must not create the false impression that once a vaccine is available the pandemic will be over, as sound public health and risk-reduction measures will still be needed to protect people as the vaccine is rolled out and population immunity is being built. It is also not known how long vaccine induced protection will last.

Ensure robust active safety monitoring as Covid-19 vaccines are rolled out

While large Phase 3 trials will help provide assurance against most serious adverse events, they may not detect very rare ones, such as was seen when Guillain-Barré syndrome occurred in approximately 1 in 100,000 recipients of the 1976 swine influenza vaccine, bringing an abrupt end to that immunization program.

In addition, clinical trials may fail to uncover unexpected adverse events that do not occur until months after immunization. Furthermore, some serious adverse events appear only after a vaccine is used in a large and diverse population, including individuals with risk factors not present in clinical trial participants. And common events like heart attacks, as well as rare diseases, can occur coincidentally following vaccination, but it is important to be sure they are not caused by the vaccine. For all of these reasons, it will be essential to have in place a highly robust monitoring system to rapidly capture safety data on new Covid-19 vaccines after they are approved or authorized.

During the 2009 H1N1 influenza pandemic, the U.S. government brought together data from a broad range of federal and private sector sources, including electronic health records, to actively monitor the safety of millions of doses of pandemic vaccines as they were rolled out and administered. These data streams were monitored by a committee of experts, including nongovernmental advisors, on a regular basis and the results were made public, helping to both ensure the vaccines were safe and maintain public confidence.

Today, even more such data are electronically available that could be used to rapidly detect and analyze potential adverse events. These systems can also help define the duration of protection of the vaccines, information needed to decide whether and when booster doses may be required.

Though the CDC has stated that overseeing Covid-19 vaccine safety will be a coordinated effort by multiple federal agencies, similar to what was done in 2009, no plan or structure has been advanced for integrated, comprehensive, interagency safety data analysis, with engagement of outside experts and public transparency. This must be done now and be fully in place when a vaccine becomes available.

Ensure the distribution and administration of Covid-19 vaccines are equitable and well-executed

The national divide in how seriously people view the Covid-19 pandemic, and the current politicization of public health communication, underscore the urgency of developing and communicating a national immunization strategy and implementation plan to ensure equity and to avert chaotic distribution of vaccines, as was experienced with Covid-19 testing and personal protective equipment.

During the 2009 H1N1 pandemic, the CDC distributed 138 million doses of vaccines to the states and territories. While much was learned and accomplished then, the logistical challenges of immunizing Americans against Covid-19 will be far greater for several reasons.

Multiple vaccines are in development, with more to come. If they succeed in clinical trials and are authorized for distribution, each vaccine will have a distinct timeline for administration. Two doses administered several weeks apart will be required for most if not all vaccines. Different vaccines cannot be mixed and matched. Tracking who received what vaccine and when will be essential.

Temperature-controlled shipping and storage will be required and may be particularly challenging for RNA-based vaccines that currently must be transported and stored at below-freezing temperatures. Sufficient quantities of essential supplies, such as needles and syringes, must be made available in tandem with the vaccine.

Individuals may decide to wait for a specific vaccine for fear of receiving one that relies on new technology or for which there have been unexplained serious adverse event reports, or may decide to wait until a significant number of other people have been safely vaccinated. A different issue will arise if early supplies of vaccines, likely to be limited, can’t keep up with the initial demand. In such a situation, individuals who stand to benefit the most should get top priority. The CDC’s Advisory Committee on Immunization Practices typically develops such recommendations.

In a departure from this norm, the National Academies of Sciences, Engineering, and Medicine were asked by the Department of Health and Human Services to develop a framework, now published, for prioritizing available doses of Covid-19 vaccines. It is not yet clear how these two groups will interact and who will adjudicate any disparate recommendations. In any event, prioritization decisions will need to be clearly explained and justified to the public.

Although the Department of Defense and the U.S. Public Health Service can play supportive roles, they lack the Center for Disease Control and Prevention’s relationships with state immunization programs that will be important to effectively coordinate distribution. To achieve equitable uptake, the vaccine must be made easily available, free of charge — including any administration costs — to diverse populations in vastly differing geographic areas, regardless of insurance or immigration status. As in the 2009 H1N1 pandemic, the more that normal systems can be used for distribution and immunization, the better for efficiency and patient trust and access.

To be successful and efficiently leverage capabilities for vaccine distribution and administration requires partnerships with both distributors of medical goods, as HHS recently announced, and with health care and pharmacy providers. Where these resources are insufficient or unsuitable, it may be appropriate to use federal resources such as the Department of Defense and U.S. Public Health Service in immunization efforts. However, any such federal engagement must be done in a collaborative manner sensitive to public perceptions that may be engendered by having a public health function fulfilled by individuals in uniform. Recent CDC guidance to states and pilot activities underway suggest collaborative approaches are being adopted, but detailed plans and public transparency and engagement are urgently needed.

Conclusion

Exciting progress is being made in the development of Covid-19 vaccines. Yet a successful immunization campaign goes far beyond having a vaccine that is safe and effective. Above all it requires public trust and interest in being vaccinated.

That trust has been undermined both by perceptions of undue haste and by intense political pressures placed on the FDA. It can be restored only by ensuring full transparency about vaccines as they are developed and distributed, protecting the FDA’s integrity and independence in decision-making, instituting a robust and transparent national vaccine safety monitoring system, and putting in place a strong and equitable vaccine distribution and immunization strategy.

Luciana Borio is an infectious disease physician, vice president at In-Q-Tel, senior fellow for global health at the Council on Foreign Relations, and former director for medical and biodefense preparedness policy at the National Security Council. Jesse L. Goodman is an infectious disease physician; professor of medicine at Georgetown University and director of its Center on Medical Product Access, Safety, and Stewardship; former chief scientist for the Food and Drug Administration; and former director of the FDA’s Center for Biologics Evaluation and Research.

  • then there’s the teensy problem of the hoardes of homeless and uninsured in my city. who will give them their jabs when we discover the vaccine needs periodic booster shots?

    I think we let health care workers and teachers and essential retail workers test the vaccine while everyone else stays home.

  • I can see if it was something like airborne Ebola, which has a mortality rate of up to 90%. Then you need to move fast and the benefit outweighs the risk. In reality, COVID-19 has a mortality rate of 0.5% -1% using the best data from countries that test extensively and do contact tracing. That is very low. In addition, nearly half (45%) of cases in the US have occurred in nursing homes, and 90% of cases in ICU are in people with commodities. So we know who the most vulnerable people are. For me, the risk of an experimental vaccine shoved through because someone wants to win an election is a very scary proposition, and I wouldn’t go near a vaccine until there is at least a year–if not more–real world data available.

  • In addition to safety, efficacy must be proven before any vaccine is approved – efficacy meaning protection against infection or mitigation of clinical disease, not antibody levels or other laboratory indicators. The public needs to see these data, i.e. how many of the 15,000 subjects in the treatment and placebo groups become infected – nothing less will do. And it will take some time after enrollment is completed for enough subjects to become infected to allow for statistical/clinical significance calculations.

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