It is increasingly clear that the United States will not follow the lead of other countries and bring the deadly COVID-19 pandemic under control.

Any return to normalcy will therefore require a vaccine and development of herd immunity. Several vaccine candidates are showing early promise, prompting the big question — when will we have a vaccine?

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To accelerate the path to market, the U.S. has purchased more than 1 billion doses of more than a half dozen vaccines that are in pre-production. Several early preclinical and clinical trials of these candidates have shown that markers of immunity — antibodies and T-cells — develop in monkeys and in humans.

This has led to a great deal of optimism that we will be able to vaccinate the population and achieve herd immunity in early 2021. A word of caution is warranted, however, as the steady stream of positive press releases from the vaccine manufacturers are not meant to show a vaccine is ready for public use, but rather to boost these companies’ stock prices and encourage further investment.

Unfortunately, there are still plenty of real hurdles to pass before a vaccine crosses the finish line. Any vaccine must be proven safe and effective prior to deployment, with an emphasis on safe.

In the largest study published thus far, of the University of Oxford and AstraZeneca chimpanzee adenovirus-vectored vaccine, just over 500 people received the experimental vaccine. More than half of participants had systemic symptoms such as chills, headache, muscle aches, fatigue and joint pain for up to a week after vaccination.

In a very small study of the Moderna mRNA vaccine, between one-third and two-thirds of all participants had mild to moderate symptoms, including fever, chills, headache, nausea and joint aches. One of the participants had a severe reaction that required a visit to a hospital.

If this degree of reactions is occurring in a relatively small number of healthy volunteers, what might happen if a vaccine is given to tens or hundreds of millions of people from all walks of life? Are there more serious reactions that occur in only one in 1,000 or one in 10,000 people? We have observed a multi-system inflammatory syndrome in some children who have experienced COVID-19 — could the vaccine elicit a similar response, like the reaction against a respiratory syncytial virus vaccine tested in the 1960s? These questions need to be answered before the public will accept a novel coronavirus vaccine.

Facing the coronavirus with facts, not fear

An equal unknown at this point is whether any new vaccine will work. None of the vaccines that are close to deployment use technologies that have ever resulted in a successful human vaccine. The leading candidates in which the U.S. has invested feature innovative approaches like nanoparticles, adenoviral vectors, and nucleic acid vaccines with either DNA or RNA. In the case of adenovirus-vectored vaccines, multiple candidates have failed over more than 30 years, and it may be difficult to provide a secondary boost as people can develop immunity against the adenovirus itself.

The data on inducing immune responses are promising, but it is not clear yet whether this will result in limited protection, modest protection or complete protection from either infection or disease. As we know from influenza vaccines, even partial protection may have benefit.

Furthermore, even if these vaccines are capable of inducing neutralizing antibodies against the virus, it is unclear how long these antibodies will remain in circulation, whether/how often boosting will be required, whether these antibodies might exacerbate disease in certain subjects, and whether these antibodies will confer protection. Essentially, these are big unknowns, and frequent failures in this field suggest that it will not be easy to achieve robust immunity.

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Manufacturing enough doses (particularly if two or more doses are needed) and distributing them to 335 million persons in the U.S. will also be a monumental task. There are likely to be delays, shortages of key materials in the supply chain, and inequities in the initial and ongoing distributions. Prioritization is likely to include critical workers first, followed by those most at risk.

How well a vaccine works in at-risk populations versus healthy volunteers may be a difficult question to answer until larger (and longer-term) studies are done. We are unlikely to have these data in 2021. A larger question may be — how much of the population is willing to get one (or more) of these vaccines? Will the novelty, lack of rigorous long-term testing, frequency of side effects, concerns (and unknowns) about effectiveness, and poor science literacy in the U.S. cause a significant portion of the population to opt out?

Despite the cautions outlined above, we think we will see vaccines become available within the next year. The FDA will probably have a lower threshold for the safety and effectiveness data for pandemic vaccines and grant provisional approvals while data are still being collected.

We are likely to see a mix of vaccines become available in the U.S., with different price points, different side-effect profiles, and some differences in both claims and actual evidence of effectiveness. Consumers will have to decide whether to get vaccinated and which product(s) to use. It is likely that there will be a patchwork of information and access available that will lead businesses and individuals to make different decisions based on factors that may be difficult to predict at this time.

Making a vaccine available is likely to be only the first hurdle — getting to herd immunity through widespread uptake in the U.S. may be the more challenging task.