Benefit of a novel 2-dose, 1-month vaccination regimen to population health

Based on the Hepatitis B Managed Markets Roundtable, April 12, 2019, San Francisco.


• Availability of a 2-dose, 1-month hepatitis B vaccination for adult populations may offer a solution to provide high rates of protective immunity

• Effective hepatitis B vaccination regimens are a cost-effective tool to manage long-term population outcomes and total cost of care

• In-depth analyses of individual organizations’ population hepatitis B vaccination compliance rates can inform the extent of opportunity for improvement

Supplement to

Volume 28, No. 9

Relatively slow protective immunity with the 3-dose, 6-month option

Roundtable participants had an immediate and positive reaction to the seroprotection curves from the first clinical trial in patients aged 18 to 55 (NCT00435812) and the second in patients aged 40 to 70 (NCT01005407), as the data demonstrated faster and higher rates with the 2-dose option in terms of peak seroprotection and time to seroprotection. The efficacy curve from the second clinical trial is shown as an example (Figure 3).

The second clinical trial was a randomized, active-controlled, observer-blinded, multicenter phase 3 study in healthy adults aged 40 to 70. This population is known to be less responsive to vaccination (Eng 2013). The 2-dose, 1-month regimen provided higher rates of protection versus the conventional 3-dose, 6-month option at every timepoint measured. The primary analysis compared the rate of protective immunity at Week 12 for the 2-dose regimen with that at Week 32 for the 3-dose option (Heyward 2013).

Roundtable participants recognized the value of the 2-dose, 1-month hepatitis B vaccination regimen in that it rapidly resulted in greater protective immunity than the conventional alternative. They were surprised to see that, in the case of the conventional 3-dose option, the last dose is the most important because it confers the majority of the immunity. The first 2 doses of the conventional alum-adjuvanted vaccine produced marginal seroprotection. This seemed counterintuitive to their shared belief that the first 2 vaccine doses would confer the majority of the immunity. Roundtable participants also noted that the immune response of the conventional 3-dose vaccine appeared to diminish slightly, resulting in a decrease in the number of seroprotected patients occurring after peak seroprotection at each dose.

“If it takes seven months to achieve protective immunity [with the 3-dose option], are we misleading people into thinking they’re safe [after 1 or 2 doses]?” —Medical Director, Regional Health Plan

Advantage of rapid seroprotection to special populations

The immunosuppressive anti-CD20 agents used in oncology (and more recently in the treatment of MS) carry the risk of HBV reactivation during treatment. Guidelines recommend that these patients should be screened for hepatitis B infection prior to the initiation of therapy (Hwang 2015). Roundtable participants noted that these patients may face a delay in initiating therapy until they have completed a hepatitis B vaccination regimen. In these instances, the difference between completing a hepatitis B vaccination series in 1 month or 6 months could be important.

Additionally, providing rapid seroprotection to healthcare workers can help reduce the risk of occupationally acquired hepatitis B infection and can help diminish concerns over liability and workplace safety.

Higher rates of protective immunity in classically hyporesponsive populations

Data from a third clinical trial (NCT02117934) showed that the 2-dose, 1-month regimen delivered higher rates of protection in known hyporesponsive populations (Figure 4). The 2-dose regimen protected 90.0% to 100% of patients in the groups studied, whereas protection rates with the conventional 3-dose vaccine were 65.1% to 93.9%, depending on patient factors (Jackson 2018). Rates of protective immunity were measured at 6 months for the 2-dose regimen and at 7 months for the 3-dose option.

Benefit of a 2-dose, 1-month vaccination option for international travelers

The CDC recommends hepatitis B vaccination for travelers to foreign destinations where hepatitis B is endemic (Mast 2006). Roundtable participants noted the chronologic challenge presented by the 3-dose, 6-month vaccine option. Very often travelers may not have allowed enough time to complete a 3-dose hepatitis vaccine series before departing on their vacation. If a trip was planned 3 months in advance, they may receive 1 or 2 of the required 3 doses but may also run the risk of forgetting to return for the 3rd dose after their travel. Roundtable participants agreed that in most cases the travel planning process would allow for sufficient time to complete a 2-dose, 1-month vaccine series.

“There’s no point vaccinating international travelers with the 3-dose option, unless for some reason somebody is going to get their immunization 6 months in advance, which is unlikely.” —CMO, Regional Health Plan

Payer and PBM participants were encouraged by the performance of the novel 2-dose, 1-month hepatitis B vaccine regimen in the adult population and recognized the value this innovation could provide.

Safety studies

Roundtable participants appreciated the fact that these clinical trials have created the largest safety database of any hepatitis B vaccine. The safety profile of both vaccines was similar in 3 pivotal clinical trials over 10,000 subjects with up to 12 months of follow-up. The percentage of subjects with an unsolicited adverse event was similar in both arms of each study. The most common local reaction was injection site pain, and the most common systemic reactions were fatigue and headache. An extensive post-hoc pooled analysis found that the novel 2-dose vaccine regimen did not increase the risk of autoimmune or cardiovascular events (Hyer 2018).


Compliance is understood to be a critical issue in all adult immunization. A Vaccine Safety Datalink study of more than 88,000 conventional 3-dose adult hepatitis B vaccine recipients showed that 81% received at least 2 doses and only 54% received all 3 doses within 1 year (Figure 5, Nelson 2009). The population in this study were members of managed care plans and several regional Kaiser Permanente plans, which are well known for their successful provider and patient engagement efforts. Real-world at-risk populations may exhibit compliance rates that are considerably lower. This fact is critical considering the third dose of a conventional 3-dose alum-adjuvanted hepatitis B vaccine at 6 months generates the majority of the protective immunity (Figure 3). Inspired by the clinical data, roundtable participants were curious to review the compliance statistics for their own member populations, both as a whole, and in at-risk subpopulations.


Vaccine performance at a population level can be estimated by multiplying the observed seroprotection rate (SPR) seen for that population in the clinical studies (where compliance was 100%) by the dosing compliance observed in the Vaccine Safety Datalink study. The result is the effective seroprotection rate, or ESPR, for that population (Box 3). The ESPR is the SPR adjusted by the size of the compliant patient population at intermediate doses or at the completion of the series. The ESPR also includes patients who achieved seroprotection despite not completing the entire regimen.


The estimated ESPR for the conventional 3-dose, 6-month regimen can be calculated by adding the individual ESPR values for each of the 3 doses. The sum of the ESPRs includes those who only received one dose but achieved protective immunity, those who received only 2 doses and were seroprotected, and those who achieved seroprotection by completing all 3 doses. The result, shown in Figure 6 below, is an estimation of the effectiveness of the 3-dose hepatitis B vaccine option at a population level.

Applying a real-world lens to hepatitis B vaccination in this way helps to illustrate an important limitation of the 3-dose regimen. Protective immunity is generated in only about half of those who begin the vaccination series when accounting for vaccination schedule compliance and the immunogenic qualities of the 3-dose vaccine option.

Population health managers in managed care organizations who are curious about the effective seroprotection rate for hepatitis B vaccination among their own plan members could recreate this calculation using compliance values derived from their plan’s data.

“I’m just throwing money down the drain if only 54% of patients get all 3 doses.” —VP, PBM


Managed care executives attending the roundtable acknowledged that the driving force for change in adult hepatitis B vaccination is likely to come from providers. Panel members also expressed the belief that the role of managed care executives should be to reduce barriers and reduce limitations on what providers may offer.

Motivation to manage hepatitis B vaccines

The panel of managed care executives expressed an expectation of contracted networks to appropriately deliver hepatitis B disease management and HBV vaccination in adults. Roundtable participants admitted that because of a range of competing priorities they have historically devoted little attention to managing vaccines other than those for influenza and pneumococcus. Instead, the decision of whom to vaccinate, and with what, has been left to provider choice.

Clinical insights gathered during the roundtable on the benefits of the 2-dose, 1-month hepatitis B vaccine regimen prompted participants to consider how a managed care organization could encourage an evolution in provider network beliefs and behavior and to explore how this change would be implemented.

Operational efficiency of the 2-dose vaccine option

The novel 2-dose hepatitis B vaccination offers adults improved seroprotection over a conventional 3-dose vaccine. It may also provide the added benefit of improving operational efficiency. Completing the 2-dose series requires one fewer office visit than the 3-dose vaccine option. Participants recognized that this could reduce the administrative burden of scheduling, lower cost by decreasing the number of missed appointments, and remove the burden of rescheduling those missed appointments. Moreover, there is a commensurate reduction in the logistical costs of stocking and managing more vaccine product on the refrigerator shelves.

Vaccination improves care quality

Quality of care is a concern shared by payer and provider organizations alike. The value of vaccination is equally well understood. Pharmacy and medical benefit decision makers unanimously acknowledged that if an NCQA HEDIS measure or a CMS Five-Star quality measure for adult hepatitis B vaccination were in place, they would not hesitate to take action to improve their plan’s quality performance scores. They would introduce system-wide performance incentives to promote changes in clinical practice and drive hepatitis B vaccination for all appropriate at-risk plan members.

Quality measures were characterized as being far more effective at driving change than guidance from professional associations or governmental bodies. Vaccination against influenza and pneumococcus in the older adult population are backed by several quality measures. The issue of vaccinating against hepatitis B was important enough that a quality measure to vaccinate infants and children was put in place nearly 30 years ago. Yet we still have a large unprotected adult population that remains vulnerable and at risk of infection.

In the absence of national quality guidelines and performance benchmarks, IDNs or Medicare Advantage plans might take more of a long-term population health perspective and be more likely to actively manage hepatitis B vaccination of their at-risk adult population. They would be more likely to realize the potential long-term cost savings of preventing cirrhosis, hepatocellular carcinoma, and liver transplantation in plan members.

The role of the internal population health champion

Roundtable participants recommended that efforts to improve hepatitis B vaccination within a health system could be bolstered by an internal champion, such as a population health expert or an infectious disease specialist. This individual could be the driving force for changing clinical practice within the health system or in contracted provider networks.

An internal champion could prove instrumental in ensuring that health system or plan members are maximizing the value of their current vaccination program. By reviewing compliance data, the population health manager could compare dosing series completion rates in the overall adult vaccine recipient population with that of at-risk subgroups (e.g., patients with diabetes). Additionally, the completion rates between sites of care (physician’s office vs retail pharmacy) could be compared. These efforts could serve as a benchmark for subsequent changes resulting from updated vaccination initiatives.

An operational framework for systematic review and change implementation

After the designated population health manager completes a review of the hepatitis B vaccination compliance data for the plan or health system, efforts can begin to build internal awareness of the opportunity by sharing the data and discussing the potential cost-effectiveness of encouraging the use of the 2-dose, 1-month vaccine option. Once leadership agrees on an appropriate course of action, organizational buy-in can be secured to over-come any operational challenges that may arise. These could include making edits to the EMR system to prompt healthcare providers to discuss the benefits of vaccination with at-risk patient populations.

Executing a switch to the 2-dose option for the adult population could include such optimization strategies as creating a communication plan for the provider network and supporting pharmacies, implementing a range of appropriate management tools, and ensuring cross-team and provider network education.

Hepatitis B vaccination efforts could be integrated with a variety of other complementary population health initiatives. Programs geared toward promoting vaccination may be improved by including hepatitis B as part of a more comprehensive approach. Similarly, liver health initiatives might benefit from expanding their scope beyond hepatitis C to include hepatitis B prevention as well.

As part of a comprehensive implementation plan, vaccine compliance data could be reassessed at a suitable timepoint (e.g., 12 months). Improvements in vaccine compliance would serve as a surrogate for enhanced protective immunity in the population. This would help document the positive change in population health and demonstrate the value of these efforts.


Managed care executives suggested a range of tactics designed to promote the implementation of a strategy favoring the 2-dose, 1-month vaccine regimen once the organizational culture was in place to manage the adult hepatitis B vaccine category.

Potential management tools for establishing the 2-dose, 1-month regimen as the preferred option

1: Verify NDCs have been added to the claims database

The first step toward changing clinical practice in favor of the 2-dose hepatitis B vaccine option is to ensure the appropriate NDCs have been correctly listed in the claims systems of the plan’s benefit design. Unnecessary billing rejections may result if the system is not accurately updated.

2: Institute an NDC block for other products

Establishing an exclusive reimbursement for the preferred agent could be achieved by implementing an NDC block for the non-covered adult hepatitis B vaccine options. This approach would carry the potential risk of alienating providers who might attempt to bill for administering residual supplies of the other agent. To avoid this possibility, roundtable participants recommended notifying contracted provider groups to explain the switch, describing how sufficient lead time will be allowed before an exclusive reimbursement for the preferred product takes place. This would provide clinicians enough time to exhaust their remaining supply of the 3-dose adult vaccine.

“We talk about how we’re really concerned about population health, and here is a simple thing to do.” —Medical Director, Regional Health Plan

3: Ensure coverage under both medical and pharmacy benefit

Another relatively simple approach proposed by round-table participants is to change the benefit design to include the 2-dose hepatitis B vaccine option in both the medical and pharmacy benefit. This would allow flexibility in the site-of-care and promote vaccine completion rates. An example of this is where a patient preparing for foreign travel might receive their first dose in the series at a clinician’s office and their final dose at a retail pharmacy 30 days later, shortly before they depart.

“That’s an interesting idea about getting the first dose in the office, the second dose in a pharmacy.” —CMO, Regional Health Plan

4: Implement an age edit to ensure appropriate patient population

Another strategy proposed for a network-driven commercial plan is to implement an age edit where reimbursement would be denied if the recipient was not in the right age range. In this approach, the conventional 3-dose vaccine option would continue to be administered in individuals from birth to <18 years old, where it is still the only approved option. Meanwhile, vaccine recipients aged 18 and older would receive the 2-dose option.

“We already have age edits where we’ll cover it down to 50 years old for [shingles vaccines], because that’s where the data are.” —Pharmacy Director, IDN


Managed care executive participants who attended this roundtable session agreed that the approval of an effective 2-dose HBV vaccine option creates an opportunity to reevaluate current practices. While inertia and barriers may exist and will vary by organization, all executives in charge of population management should reexamine their efforts toward hepatitis B prevention. The first step is to investigate the vaccine compliance of plan members, evaluate current management tools, and identify an appropriate approach for each provider network in order to encourage a shift in clinical behavior toward the 2-dose hepatitis B vaccine regimen for at-risk adults.

This MANAGED CARE Special Supplement, “Strategies to Optimize Adult Hepatitis B Vaccination: Benefit of a 2-dose, 1-month Vaccination Regimen to Population Health,” was produced with support from Dynavax Technologies Corporation


• Historically, managed care executives have not actively engaged in vaccine decision-making; however, advances in hepatitis B vaccination may help optimize vaccination strategies from a population health perspective

• Roundtable participants were encouraged by the clinical performance of a 2-dose, 1-month hepatitis B vaccination in the adult population

• Payer and IDN participants shared easy-to-implement management techniques to encourage utilization of a preferred option in the adult hepatitis B vaccine category:

• Designating an internal population health champion to promote improved strategies in hepatitis B vaccination

• Examining internal vaccine compliance data to identify opportunities to maximize the value of vaccination programs

• Including hepatitis B vaccines on both the medical and pharmacy benefit to allow flexibility in site of care and promote dose series completion

• Implementing NDC blocks with 1-year advance notice of switch to preferred agent

• Instituting an age edit whereby vaccine recipients ≥18 years old would be given a 2-dose vaccine


• Managed care decision makers rely on healthcare providers to recognize and act on a changing environment in hepatitis B vaccination

• Roundtable participants were encouraged by the value of the 2-dose, 1-month HBV vaccination in the adult population (net cost and performance)

• Techniques for managing the hepatitis B vaccine category and favoring the 2-dose vaccine option for adults were explored and included:

• Designate an internal population health champion to drive change

• Examine internal vaccine compliance data to identify opportunities to maximize the value of vaccination programs

• Ensure HBV vaccines are on both the medical and pharmacy benefit to allow site-of-care flexibility and promote dose series completion rates

• Institute an NDC block with advance notice of switch

• Implement an age edit to ensure vaccine recipients 18 years of age and older are given the 2-dose vaccine option


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