What Does a Multi-Dose Series Mean for the COVID-19 Vaccination Effort?

Introduction

There are currently two COVID-19 vaccines authorized for use in the United States, both of which require a two-dose series (see Table 1). As efforts to promote equitable and rapid distribution and uptake of the vaccine in the U.S. intensify, one key challenge is ensuring people get both the first and second dose. In fact, in the COVID-19 vaccine playbook provided to states by the Centers for Disease Control and Prevention (CDC), the issue of second dose reminders was identified as a key area to be addressed.  In the context of routine immunization, multi-dose vaccine series are relatively common, but have also presented challenges for ensuring vaccine series completion where in many cases, there is a drop-off in uptake between the first and subsequent doses. Additionally, as COVID-19 vaccines have rolled out, there have been discussions about the appropriateness of flexibility in dosing schedules to accelerate first doses for more people; there is also a likelihood that a third vaccine from Johnson & Johnson, that uses only one dose, could be authorized soon. This issue brief examines key issues related to multi-dose vaccination series generally as well as issues specific to COVID-19.

How common are multi-dose vaccines?

Multi-dose vaccinations are very common. In fact, nearly all vaccines recommended for children and adolescents and many adult vaccinations, require a series of more than one dose (Table 2).

Why do some vaccinations require multi-dose series?

In some cases, multiple doses are necessary to achieve the highest possible levels of immunity, whereas in others, a second dose is administered because not all individuals respond sufficiently to a single dose. In addition, following the primary vaccination or vaccination series, certain vaccines require a booster for all people or certain groups of people after a period of time to improve waning immunity.

The number of doses in a vaccination series can be the same for everyone or differ based on risk group, age, and other factors. For instance, the human papillomavirus (HPV) vaccine is given in either two or three dose series, depending on age of initial vaccination.

The COVID-19 vaccines that have been authorized in the U.S. require a two-dose series to achieve highest levels of immunity. There is no recommendation for a booster shot at this time but Moderna, one of the manufacturers of an authorized vaccine states that while its vaccine is expected to be protective against COVID-19 variants, the company is exploring whether a booster can offer additional protection and Pfizer, the other manufacturer, has indicated that boosters are likely needed.

Is the annual flu shot an example of a multi-dose vaccination?

A vaccine with a multi-dose series differs from the annual flu shot. While flu shots are needed annually to maintain optimal levels of protection, the main reason subsequent shots are given is because the influenza vaccine is updated each year to account for virus mutations. The effectiveness of the influenza vaccine varies from year-to-year, often because there are differences between the strains targeted by the vaccine and the strains circulating and infecting people each year.

It is not yet known if COVID-19 vaccines will need to be updated annually (or at another interval), as we do with the flu shot, or if there will be a need for a booster shot later on. Given the rise of several viral variants in numerous countries around the world including the U.S., work has already begun on producing and setting up the regulatory approval pathways for a booster shot for some of the COVID-19 vaccines already authorized. For the time being, however, no additional doses beyond the first two are recommended at this time.

What do we know about uptake of multi-dose vaccinations?

In general, there is a decline in uptake between the first and subsequent doses of vaccines, especially for those provided to adolescents and adults. For example, the CDC recommends the multi-dose HPV vaccine at age 11 or 12, with two doses given six months apart. It is recommended that older teens and young adults, who initiate the series later, receive three doses. Multiple studies have shown that uptake of the HPV vaccines declines for 2^nd and 3^rd doses. For instance, a CDC analysis found that among adolescents 13-17 years old, 72% received ≥ 1 dose in 2019 but the series completion rate fell to 54%. In recognizing these challenges in part, researchers are studying the potential of a one-dose HPV vaccine, particularly for low and middle income countries, which have fewer financial resources for implementing vaccination programs and where cervical cancer prevalence is higher than the United States.

Qualitative research on HPV vaccination in the U.S. shows most parents who did not obtain their teen’s second or third dose intended to do so. Most said they did not because they were not reminded to come back for second doses by their providers, even though they expected a reminder. Parents also said that sometimes they forgot about the subsequent shot(s) or did not have time to return. This contributed to the drop off between first and subsequent vaccinations within a series.

There is also a drop off in acquisition of the booster for the MenACWY vaccine to prevent Meningitis, which has a long interval between doses. The first dose is recommended at age 11 or 12, while the booster is recommended at age 16. CDC analysis from 2019 shows that nearly nine in ten (89%) adolescents 13-17 had the initial dose of the MenACWY vaccine; however, among adolescents aged 17 years, just over half (54%) had received the booster dose.

A third example is Shingrix, the vaccine recommended for adults over 50 to prevent shingles. Shingrix is provided in two doses over the course of six months and offers some insight on multidose vaccines in adults. Recent KFF analysis found that one-quarter of Medicare beneficiaries (26%) who received an initial dose of Shingrix between January and June 2018 did not receive the second dose within the recommended timeframe.

Does uptake and completion of multi-dose vaccination series differ by race and ethnicity?

In several cases, racial and ethnic disparities are observed in multi-dose vaccine series completion. Series completion rates are lower among Hispanic adolescents compared to others for some vaccines, including MMR, Hepatitis B, and Varicella, though in other cases adolescents of color have completion rates comparable to White adolescents.

Looking to an adult vaccination, disparities are stark in Shingrix vaccine completion rates among Medicare beneficiaries. White beneficiaries saw higher completion rates (76%) than Hispanic (58%), American Indian/Alaska Native (61%), Black (61%), and Asian/Pacific Islander beneficiaries (69%).

Paying careful attention to these disparities in COVID-19 vaccine uptake and series completion will be critical, particularly as the pandemic has also taken a disproportionate toll on communities of color, including with higher death and case rates for certain groups. In addition, some people from immigrant communities, many of whom have been targeted in recent years by anti-immigration policies and discrimination, may be fearful about the vaccine monitoring process. This is especially relevant as vaccine providers will collect personal information to assist in efforts to get people to return for the second dose.

Indeed, initial data from state-reported vaccinations by race/ethnicity suggest emerging racial disparities in vaccination rates, with Black and Hispanic people receiving smaller shares of vaccinations than White people, despite accounting for disproportionate shares of cases and deaths. Notably, in their recently released COVID-19 Response Plan, the Biden Administration included protecting “those most at risk and advance equity, including across racial, ethnic and rural/urban lines” as one of the plan’s 7 goals.

What are possible unique challenges associated with a multi-dose COVID-19 vaccine?

The U.S. effort to distribute and administer the multi-dose COVID-19 vaccines has been met with unique challenges. Never before has such a large-scale vaccine rollout taken place with such urgency and aimed at so many people. Rollout has been hampered by a range of barriers, while some of these have to do with health care delivery in the U.S. (e.g. a fragmented health system, underfunded public health infrastructure, etc.) others that relate to the multidose nature of the currently authorized vaccine series and challenges are already surfacing.

Manufacturers and the FDA recommend the second dose is given either three or four weeks after the first, depending on which vaccine was administered.  (See Table 1). While a single dose offers some protection (see Table 1) it is below levels needed to achieve herd immunity and it is not known exactly how long protection lasts. Therefore, getting individuals to return for a second dose as soon as they are eligible will offer the best route to achieve the highest level of protection as quickly as possible.  However, as the initial distribution of COVID-19 vaccines has been going more slowly than originally intended, there have been discussions related to dosing and spacing from public health officials, researchers, clinicians, and advocates.

Challenges related to the COVID-19 vaccine include:

• Confusion around multiple vaccination options. Currently, the two authorized vaccines are made by different manufacturers and have different recommended timetables for second vaccination (See Table 1). The recommendation in the U.S. is to get a first and second dose vaccination from the same manufacturer, though CDC guidance now permits some flexibility in “exceptional situations in which the first-dose vaccine product cannot be determined or is no longer available.” Differences in name and interval in the authorized vaccines complicate public health messaging and necessitates that some combination of individuals, providers, and localities/states keep track of who has had which vaccination and when. In addition, there could be a third COVID-19 vaccine from Johnson & Johnson authorized in the coming weeks requiring only a single dose, which would simplify the dosing schedule for recipients of that vaccine but would add further complexity to overall messaging about who should get which vaccine, and when.
• Key stakeholders have been grappling with how to improve timely access to the two doses. Questions have been raised about how to best accelerate rollout in the context of significant supply limitations and rising infections. Some have urged the use of all available vaccine for first doses while others would set aside a reserve to ensure second doses are completed at the recommended interval for all individuals. The Trump Administration initially held back significant supply to ensure second doses. However, due to the slow rollout and increasing spread in the US, many felt distribution needed to be sped up. The Biden Administration’s COVID-19 Plan pledges to “end the policy of holding back significant levels of doses, instead holding back a small reserve and monitoring supply to ensure that everyone receives the full regimen as recommended by the FDA.”
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  There have been separate questions about whether the interval between first and second doses can be longer than indicated in the EUA to speed up distribution of first doses to more people, as is the case in the UK and other countries.  U.S. officials have rejected this approach to date.
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  In response to some of these discussions, FDA issued a statement emphasizing that the vaccines should be administered according to how they have been authorized and that changes to dosage or dosing schedule “not supported by adequate scientific evidence may ultimately be counterproductive to public health.”  Tony Fauci, Chief Medical Advisor to President Biden, has reiterated this sentiment in White House COVID-19 Response Team briefings.
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  At the same time, recognizing the real world context in which the vaccine rollout is occurring, CDC guidance notes that while second doses “should be administered as close to the recommended interval as possible….if it is not feasible to adhere to the recommended interval, the second dose…may be scheduled for administration up to 6 weeks (42 days) after the first dose.”

• Unlike many vaccines, which are scheduled in conjunction with wellness visits, at this point, COVID-19 vaccinations are scheduled separately as unique events. This differs from many of the childhood/adolescent vaccinations that require a series of injections but are scheduled alongside office visits, raising additional concerns about people returning for second doses.
• Side effects may deter individuals from returning for a second dose. As with any vaccination, side effects occur for some individuals. CDC describes common COVID-19 vaccine side effects as pain and swelling in the arm of the injection site and fever, chills, tiredness, and headache, similar to what is described for the flu shot. While side effects appear to be more mild with the first dose in the series than the second, some people who experience COVID-19 vaccination side effects with the with first dose may be deterred from completing the series. Indeed, nationally representative polling has found that among those who are probably or definitely not planning to get a COVID-19 vaccine, 81% say worries about side effects are a reason for this position and 59% say it is a major reason.
• Underlying resource inequities may make it more difficult for some groups to receive the second dose. Access to resources including the internet, email, transportation, and having an existing relationship with a health care provider could all influence the ease of accessing and likelihood of receiving a second dose. People of color, low-income, and other underserved groups are less likely to have access to these resources that will play a key role in second dose reminders and access. To the extent that these unmet needs influence vaccine uptake and series completion, disparities in COVID-19 cases and deaths could widen.
• Additionally, we do not yet know how the pandemic will impact multi-dose vaccine series completion more generally. Vaccines are often provided as a part of routine care but the COVID-19 vaccine is being provided with great urgency in the midst of a pandemic. On the one hand, completing the vaccine series in midst of the pandemic could be more challenging for a range of reasons. On the other hand, people may be more aware of the need for two COVID-19 vaccine doses given extensive coverage in the media and elsewhere.

What do we know about effective messaging to boost vaccine uptake and ensure series completion?

Securing public trust and motivating large shares of the population to get vaccinated against COVID-19 is essential in curbing the epidemic, and ensuring that people return for their second dose will be critical to achieving the highest levels of efficacy. It will be important to engage in a range of activities to encourage individuals to get vaccinated. In addition to adopting clear and persuasive messaging to ensure sufficient vaccine uptake in the first places, public health stakeholders will also need to focus on vaccination series completion. Good intentions may not be enough. In fact, CDC’s interim playbook suggests a number of avenues that vaccine providers and recipients can use to encourage and facilitate uptake of second doses of COVID-19 vaccines:

• Schedule appointment for second dose at time of first dose
• Complete vaccination cards with accurate information, including the manufacturer, date of first dose, and date of appointment for second dose
• Advise vaccine recipients to keep and bring card to second appointment in case data systems are not operational
• Suggest that recipients take a picture of the card and enter second appointment into electronic calendar if they use one
• Maximize the capacity of Immunization information systems and electronic health record (EHR) systems to send reminders about second dose appointments. Given that some COVID vaccine providers will be new to vaccine administration and may not be familiar with immunization registries, it will be important to ensure that providers are trained and know how to use the information systems to issue reminders for second dose appointments.
• Consider automated phone calls, emails, and text messages to send reminders
• Use health plan claims data to monitor dosages and remind enrollees about second dose

A combination of approaches may be important because different strategies are likely to be more effective with different populations, particularly those groups with highest levels of vaccine hesitancy and government/medical mistrust as well as those with fewer resources. Research shows that seniors are less likely to have a smart phone or use a computer, so solely relying on this technology for second dose reminders may not be as effective in reaching this high priority population as it is for others. The same consideration will apply to other groups with limited access to technology. Provider recommendation for vaccines is also associated with increased vaccination rates , and this could be particularly important for targeting those who are who are most skeptical about vaccination, at greatest risk for infection and severe disease, which includes people of color and older adults.

Discussion

Widespread adoption of COVID-19 vaccines is a public health imperative. To date, the rollout has been challenging for many reasons and may be further complicated by the multi-dose nature of the two currently authorized COVID-19 vaccines. Past vaccine efforts for other multi-dose vaccines have shown that there is often a drop off between the first and subsequent doses. Additionally, in the context of COVID, so far there are varying dose schedules for the different products, and concerns about supply. Finally, COVID-19 vaccination is being rolled out in the midst of a global pandemic which is quite different than routine vaccination. While there are always challenges in implementing a new vaccination program, the combination of these factors may pose obstacles to completing a multi-dose COVID-19 vaccine series and will require focused efforts to overcome.