MEETING OF THE ADVISORY 

COMMITTEE ON IMMUNIZATION 

PRACTICES (ACIP) 

MAY 5, 2021 

SUMMARY MINUTES 

TABLE OF CONTENTS

MEETING PURPOSE ................................................................................................................ 2

Wednesday: May 5, 2021 .......................................................................................................... 2

WELCOME AND INTRODUCTIONS ...................................................................................... 2

RABIES VACCINE.................................................................................................................. 2

DENGUE VACCINES ............................................................................................................17

Certification...............................................................................................................................28

ACIP Membership Roster .........................................................................................................29

Acronyms Used in the Document..............................................................................................38
ACIP Meeting Summary May 5, 2021

2

MEETING PURPOSE

The United States (US) Department of Health and Human Services (HHS) and the Centers for 

Disease Control and Prevention (CDC) convened the regularly scheduled quarterly meeting of 

the Advisory Committee on Immunization Practices (ACIP) on May 5, 2021. The meeting took 

place remotely via Zoom and teleconference. This summary document provides a brief overview 

of the meeting, which focused on the topics of rabies vaccine and dengue vaccine. 

WEDNESDAY: MAY 5, 2021

WELCOME AND INTRODUCTIONS

Dr. José R. Romero (ACIP Chair) called to order and presided over the meeting. He conducted 

the roll call during which one potential conflict of interest (COI) was declared by voting member

Dr. Camille Kotton, who served on a data safety monitoring board (DSMB) for pneumococcal 

vaccine for Merck. A list of Members, Ex Officios, and Liaison Representatives is included in the 

appendixes at the end of this summary document.

Dr. Amanda Cohn (ACIP Executive Secretary) welcomed everyone and noted that an agenda 

for the day soon would be posted to the ACIP website. She indicated that the next virtual 

Emergency ACIP meeting was scheduled for May 12, 2021. She explained that there would be 

an oral public comment session at approximately 1:00 PM Eastern Time (ET). Given that more 

individuals registered to make oral public comments than could be accommodated, selection 

was made randomly via a lottery. Those individuals who were not selected and any other 

individuals wishing to make written public comments may submit them through 

https://www.regulations.gov using Docket Number CDC-2021-0025. Further information on the 

written public comment process can be found on the ACIP website. As noted in the ACIP 

Policies and Procedures manual, ACIP members agree to forgo participation in certain activities 

related to vaccines during their tenure on the committee. For certain other interests that 

potentially enhance a member’s expertise, CDC has issued limited conflict of interest (COI) 

waivers. Members who conduct vaccine clinical trials or serve on DSMBs may present to the 

committee on matters related to those vaccines, but are prohibited from participating in 

committee votes. Regarding other vaccines of the concerned company, a member may 

participate in discussions with the provision that he/she abstains on all votes related to that 

company. ACIP members stated COIs at the beginning of the meeting, and no votes were taken 

during this meeting.

RABIES VACCINE

Introduction

Dr. Sharon Frey (Chair, ACIP Rabies WG) introduced the Rabies Session during which she 

provided an update on the activities of the Rabies Vaccines Work Group (WG). To recap the 

WG’s activities during the February 2021 ACIP meeting as they related to Pre-Exposure 

Prophylaxis (PrEP), the WG addressed questions raised by the ACIP about PrEP costs; 

summarized clinical guidance presented at previous meetings; and recapped policy questions, 

evidence tables, and Evidence to Recommendation (EtR) Frameworks. Additionally, the ACIP 

committee requested a fourth group to be added to the PrEP table so that persons with risk for 

rabies ≤ 3 years would be included in their own risk category. Also during that meeting, ACIP 
ACIP Meeting Summary May 5, 2021

3

voted on 2 PrEP policy questions for persons ≥ 18 years of age and deferred the vote for 

persons < 18 years of age to a future ACIP meeting.

Dr. Frey shared/reviewed the new table with the fourth group added. The first two groups

include individuals with elevated risk for unrecognized and recognized exposure. The difference 

between the first two groups is that the risk of virus exposure is continuous in the first group and 

episodic in the second group. The third group has elevated risk of a recognized exposure that is 

sustained. The fourth group has elevated risk of recognized exposure that is not sustained. The 

fifth group was the group that was requested to be added during the February 2021 ACIP 

meeting, which is at low risk of contracting rabies (i.e., the general population).

Since the last ACIP meeting, the WG continued to discuss topics related to PrEP and postexposure prophylaxis (PEP), including discussing questions raised by the ACIP about rabies 

PrEP and children. In addition, they discussed communication of updates to the 2008 ACIP 

recommendations according how, when, and through what channels to make these 

communications to stakeholders and how to ensure communications are clear and can be 

smoothly implemented by end-users. Specific to PEP, the WG discussed which additional topics 

should be considered by the WG. For example, they are looking at immunogenicity in children

and may look at immunogenicity in the elderly.

The WG’s goal for this session continued along the same lines for PrEP, with presentation of

the data reviewed by the WG about PrEP and children, presentation of the two policy questions 

voted on during the February meeting for adults and the proposed questions for children in 

anticipation of a vote during the June 2021 ACIP meeting. In addition, this session included a 

presentation of background information about PEP and a general approach to PEP. In terms of 

the anticipated timeline, the WG anticipates entertaining an ACIP vote on PrEP as it relates to 

children; presenting the WG’s interpretation of data about Rabies Immune Globulin (RIG) and 

PEP schedules, including Grading of Recommendation Assessment, Development and 

Evaluation (GRADE) and EtR during the June 2021 ACIP meeting; and presenting clinical 

guidance PrEP and PEP schedule deviation. This work may continue into October 2021 

depending upon what transpires.

Rabies PrEP in Children 

Agam Rao, MD (CAPT, USPHS; Co-Lead Rabies ACIP WG; CDC/NCEZID) presented on 

rabies PrEP in children. There are multiple levels to prevent human rabies in the US, including 

avoidance of risky behavior such as avoiding international tourist destinations that are known to 

have rabid animals, vaccination of pets and wildlife, and proper use of personal protective 

equipment (PPE) when handling bats for occupational responsibilities. Over the course of a 

lifetime, the average person in the US has no rabies exposures simply because these measures 

are in place. Therefore, the average person has no need for PrEP. If those barriers fail, there is 

PEP. PEP involves rabies immune globulin and an affordable vaccine series. Prompt and

appropriate PEP alone and response for an exposure is typically enough to save lives when an 

exposure occurs. While PrEP is indicated for specific populations in the US, this does not 

negate the need for PEP if an exposure occurs.
ACIP Meeting Summary May 5, 2021

4

The ACIP does not recommend PrEP for the general US population. It is given before an 

exposure, but does not negate the need for PEP if an exposure occurs and is indicated for only 

select populations and for specific reasons. There are 3 reasons that PrEP is recommended for 

select populations. The first is that when rapid PEP administration is not enough. This can occur 

when someone is exposed to an extremely high concentration of rabies virus exposure or an 

unusual rabies virus exposure like an aerosolized exposure. Aerosolized exposures do not 

occur naturally. They typically would occur only within a laboratory under unusual 

circumstances. Second are unrecognized rabies exposures. These can happen when, for 

example, someone who frequently interacts with bats and frequently feels them brushed up 

against them may not realize when they have had a bite from a bat. That can go undetected, 

given that a very small puncture wound from a bat tooth is only about 2 to 10 millimeters and the 

bite strength is approximately 2 pounds of pressure. Someone might awaken from sleep and not 

realize they have been bitten, or a biologist might enter a high-density bat environment like a bat 

cave may not find it atypical when they get swarmed by bats. The third reason that PrEP is 

recommended for select populations is challenges with the access to PEP. RIG is not available

in some developing countries. Rabies vaccines may be available only in a capital city of a 

developing country, resulting in a delay of PEP administration. For that reason, travelers, 

particularly children, are recommended to get PrEP.

In recognized exposures, the reason for PEP is clearly different from the previous reasons 

mentioned and the primary reason that children ever would receive PrEP. A sequence of events

for many travelers illustrates what could happen to a traveler. An ideal scenario would be one in 

which someone receives a bite from a rabid dog while within the capital city of a developing 

country, quickly receives thorough wound washing with soap and water, and has quick access 

to PEP. While PEP should be administered promptly, there is no specified time period within 

which PEP should be administered after an exposure. The ideal scenario is for a person in a

capital city with access to RIG and vaccine to complete the entire series by Day 45. The 

problem occurs when someone is visiting/bitten in a rural area and does not begin traveling to a 

major city where PEP is available until the following day and it may take a significant period of 

time before they can actually identify a source for rabies vaccine and there may not even be 

RIG available, which would delay their care. It is for the second scenario that rabies PrEP is 

recommended. The Yellow Book specifies that PrEP should be recommended for travelers

based on the occurrence of animal rabies in the country of destination; availability of anti-rabies 

biologics; intended activities of the traveler, especially in remote areas; and the traveler’s

duration of stay. Children, in particular, should be offered PrEP when indicated. PrEP in children 

is an important issue. The Yellow Book states the following:

“Children are at higher risk for rabies exposure and subsequent illness because of their 

inquisitive nature and inability to read behavioral cues from dogs and other animals. The 

smaller stature of children makes them more likely to experience severe bites to high 

risk areas, such as the face and head. Also contributing to the higher risk is their 

attraction to animals and the possibility that they may not report an exposure.”

1

1

*Yellow Book; https://wwwnc.cdc.gov/travel/yellowbook/2020/travel-related-infectious-diseases/rabies; accessed on 4/20/21
ACIP Meeting Summary May 5, 2021

5

The benefits of receiving PrEP is that no RIG is needed if an exposure occurs. Only a 2-dose 

PEP vaccine series is needed once an exposure occurs. Those are given on Day 0 and Day 3 

instead of the 4-dose PEP rabies vaccine series which is given at Days 0, 3, 7, and 14. This can 

be beneficial for travelers to some developing countries where RIG may not be available, where 

the rabies vaccines may take time to access, and where a 2-dose series is easier to get than a 

4-dose series because of travel itineraries.

The WG clearly recognizes that children and rabies represent an important issue. For that 

reason, they took the approach of setting some expectations for what they would consider to be 

acceptable in a PrEP series. First, primary immunogenicity had to be demonstrated by given 

series. That is, the minimum acceptable antibody titer threshold would have to be reached 

within 14 days of series completion. Second, the WG determined that a high proportion of 

patients will have to achieve primary immunogenicity. The rationale behind this point was that if 

primary immunogenicity or seroconversion is achieved after completion of the vaccine series

and an exposure then occurs, there will be a rapid anamnestic response. This anamnestic 

response would occur regardless of the time from PrEP to exposure. As long as primary 

immunogenicity was reached, the WG could be confident that an anamnestic response would 

occur after an exposure.

The WG felt that factors that do not impact an anamnestic response are the number of vaccine 

doses over that needed to achieve primary immunogenicity, the number of bites or scratches to 

a patient, the severity of bites or scratches, the location of those, and the size of the exposed

person. Anamnestic response is an all-or-none response that occurs quickly after an exposure.

That is why the number of vaccine doses to push the titer up higher than the minimum antibody 

titer does not contribute to the response. Recognizing that children are an important population 

for rabies PEP, the WG considered whether there is any reason to believe that children have a 

different response to rabies vaccines than adults. To that end, the WG performed a systematic 

review in 2019 to determine if pediatric response to various rabies vaccine series is inferior to

that of adults. Over 12 papers were identified from multiple databases that met the WG’s search 

criteria. Of those, 7 involved children <2 years of age and 7 involved children 2-18 years of age. 

The age ranges of the patients were 2 months to 17 years. The WG concluded that geometric 

mean titers (GMTs) in children are the same or higher than those in adults for any given series.

In addition, GMTs stay higher for longer in children. Thus, there is no reason to suspect 

suboptimal immunogenicity in children compared to adults.

To point out a few key items in the manuscripts reviewed by WG that indicated robust 

response in children, diverse ages are represented in these manuscripts. The first study by 

Chatchenet et al (2017) involved children <2 years of age and there were 68 subjects. This 

study concluded that comparison to 18-24 year old subjects in Thailand studied similarly, “these 

findings suggest that the immune responses of the toddlers were better than those of young 

adults.” This is evidence for long-term induction of protective antibodies by PrEP.

2 The second 

study by Fridell et al (1984) had children <5 months of age to 15 years of age. This study 

concluded that, “There was good antibody response with titers (EU/mL) higher than those in 

adults.”

3 The third study by Kamoltham et al (2011) included 703 children aged 5 to 8 years. In 

this study,100% of children had titers >0.5 IU/mL at 1, 3, and 5 years after ID booster to 2 or 3 

2 Chatchenet al; 2017 “Long-term protective rabies antibodies in Thai children after pre-exposure rabies vaccination”; SE Asian 

Journal of Trop Med & Public Health

3 Fridell et al (1984) “Pre-exposure prophylaxis against rabies in children by human diploid cell vaccine”; Lancet
ACIP Meeting Summary May 5, 2021

6

dose ID primary series 14 days after booster and that this was safe and immunogenic.

4 The 

remaining studies and numbers of children in each are listed below:

❑ Lang et al (1999 and 1997): 84 Vietnamese children 24 months of age5

❑ Lang et al (1999): 240 children in Vietnam who were 2, 3, and 4 months of age6

❑ Kamoltham et al (2007): 206 school-aged children in Thailand7

❑ Lang et al (2009): 72 children 2, 3, 4 months and 1 year8

❑ Li et al (2015): 243 children 6 to 17 years of age9

❑ Pengsaaet al (2009): 200 healthy children aged 12 to 18 months in Thailand10

❑ Sabchareonet al (1998): 190 school children aged 5 to 1211

❑ Sabchareonet al (1999): 400 schoolchildren; 100% of children had titers >0.5 IU/mL at day 

21 (i.e., 14 days after the 2nd vaccine)12

❑ Shanbaget et al (2008): 175 school children 6 to 13 years of age; 100% had RVNA 

concentrations above 0.5 IU/mL after completion of the 3 dose series13

❑ Vienet et al (2008): 4 to 8 months primary series and 16 to 20 months later; all children 

mounted an anamnestic response to challenge14

The WG came away from this convinced of the conclusions that have been made in the Yellow 

Book stating that, “Pregnancy is not a contraindication to PEP. In infants and children, the dose 

of HDCV or PCEC for preexposure or PEP is the same as that recommended for adults. The 

dose of RIG for PEP is based on body weight (Table 4-18)” and also in the 2008 ACIP 

recommendations stating that, “Children should receive the same vaccine dose (i.e., vaccine 

volume) as recommended for adults.” Notably, the reason that there are so many very young 

included in some of these studies is that the idea of introducing rabies vaccine PrEP into the 

routine childhood vaccine series was being considered. That is why the vaccination schedule for 

children has not deferred for from those for adults.

4 Kamoltham et al; 2011 “Immunogenicity of simulated PCECV Post-exposure doses 1, 3, and 5 years after 2-dose and 3-dose 

primary rabies vaccination in schoolchildren; Advances in Preventive Medicine

5 Lang et al; 1999 and 1997 “Booster vaccination at 1 yr with rabies vaccine associated with DTP-IPV in infants living in rabies 

endemic country” Journal of tropical pediatrics “Randomized feasibility trial of pre-exposure rabies vaccination with DTP-IPV in 

infants” The Lancet

6 Lang et al; 1999 “Immunogenicity and safety of low-dose ID rabies vaccination given during an Expanded Programmeon 

Immunization session in VietNam: results of a comparative randomized trial; Transactions of the Royal Society of Tropical 

Medicine and Hygiene

7 Kamoltham et al; 2007 “Pre-exposure Rabies Vaccination Using Purified Chick Embryo Cell Rabies Vaccine Intradermally is 

Immunogenic and Safe.” Journal of Pediatrics

8 Lang et al; 2009 “Pre-exposure purified vero cell rabies vaccine and concomitant routine childhood vaccinations: 5-year postvaccination follow-up study of an infant cohort in Vietnam” Journal of trop Pediatrics

9 Li et al; 2015 “Immunogenicity and safety of purified chick-embryo cell rabies vaccine under Zagreb 2-1-1 or 5-dose Essen 

regimen in Chinese children 6-17 yrsold and adults >50 yrs: a randomized open-label study Human vaccines and 

immunotherapeutics

10 Pengsaa et al; 2009“A Three-Year Clinical Study On Immunogenicity, Safety, and Booster Response of Purified Chick Embryo Cell 

Rabies Vaccine Administered Intramuscularly or Intradermally to 12- to 18-Month-Old Thai Children, Concomitantly With Japanese 

Encephalitis Vaccine” Pediatric Infectious Diseases Journal

11 Sabchareon et al; 1998 “Persistence of antibodies in children after ID or IM administration of PrEPprimary and booster 

immunizations with purified Vero cell rabies vaccine.” The Pediatric Infectious Disease Journal

12 Sabchareon et al; 1999 “A New Vero Cell Rabies Vaccine: Results of a Comparative Trial with Human Diploid Cell Rabies Vaccine 

in Children” Clinical Infectious Diseases

13 Shanbag et al; 2008 Protecting Indian schoolchildren against rabies: pre-exposure vaccination with purified chick embryo cell 

vaccine (PCECV) or purified verocellrabies vaccine (PVRV); Human Vaccine

14 Vien et al; 2008 Long-term anti-rabies antibody persistence following intramuscular or low-dose intradermal vaccination of young 

Vietnamese children Transactions of the Royal Society of Tropical Medicine & Hygiene
ACIP Meeting Summary May 5, 2021

7

After the WG confirmed that the approach was that any PrEP schedule recommendations made

for adults would be applicable to children as well, they presented the following 2 

recommendations to the ACIP (as a reminder, ACIP voted on and passed both of these 

recommendations for persons ≥18 years of age only):

1. ACIP recommends a 2-dose [0, 7 days] intramuscular rabies vaccine series in 

immunocompetent persons for whom rabies vaccine pre-exposure prophylaxis (PrEP) is 

indicated.

2. ACIP recommends an intramuscular booster dose of rabies vaccine, as an alternative to 

a titer check, for immunocompetent persons who have sustained and elevated risk for 

only recognized rabies exposures (i.e., those in risk category #3 of rabies PrEP 

recommendations table). The booster dose should be administered no sooner than day 

21 but no later than 3 years after the 2-dose PrEP series.

The WG’s thought process in developing this first recommendation was that with the primary [0, 

7 days] IM series there are robust data demonstrating the boostability for up to 3 years. This 

was presented in the GRADE table during the October 2020 and February 2021 ACIP meetings. 

The advantages for travelers, including children, are that travelers typically do not have enough 

time to receive the 3-dose series because Dose 3 is due no sooner than Day 21. Often, travel 

medicine clinic appointments are not scheduled far enough in advance to get the third dose. It is 

known from the travel experts who served on the WG that in many cases, they do not initiate 

PrEP because they cannot complete the entire series. Another advantage for travelers is that 

the proposed recommendation is believed to facilitate more travelers getting vaccinated when it 

is indicated to do so.

To highlight a couple of key items from the previously presented GRADE and the EtR, the 

evidence profile in the GRADE assessment for the outcome of “immunogenicity” as measured

by a titer ≥0.5 IUs/mL, the WG assessed the body of evidence from randomized controlled trials 

(RCTs) and not non-randomized study separately and concluded that there is moderate 

certainty (Level 2) about immunogenicity for the RCTs. A total of 264/264 people seroconverted

with the [0, 7 days] series compared to the [0,7, 21,28 days] series that also achieved 100% 

seroconversion. The WG could have stopped at that because the certainty was Level 2; 

however, they moved forward to evaluate the observational studies identified in the search as 

well.

For PrEP Policy Question #1, the WG identified 10 additional studies that compared a 2-dose to 

a 3-dose primary series. The mean age of children in the Sabchareon et al (1999)15 was 10 

years of age, with a range of 5 to 13 years of age. The intervention included 190 persons. After 

a [0, 7 days] series, 100% of these children had antibody titers ≥0.5 IU/mL and 100% had titers 

≥0.15 IU/mL. The reason the authors included both ≥0.15 IU/mL and ≥0.5 IU/mL was because 

they estimated that ≥0.15 IU/mL was closer to the ACIP recommendation for the minimum

antibody titer level. However, the ACIP is planning to move toward the ≥0.5 IU/mL as well.

Regardless, this study showed that appropriate titers were reached 100% of the time in these 

children.

15

 Sabchareon A, Lang J, Attanath P et al. A new vero cell rabies vaccine: Results of a comparative trial with human diploid cell

rabies vaccine in children. Clin Infec Dis. 1999; 29: 141-9.
ACIP Meeting Summary May 5, 2021

8

The WG’s thought process for the second recommendation was that based on what is known 

about immunology, there is every expectation that boostability is preserved beyond 3 years.

However, because rabies is nearly 100% fatal and ACIP advised the WG during previous 

meetings to ensure that there were robust data for any proposed change to the existing

recommendations, the WG took the very conservative and cautious approach. The WG knows 

from the data they have reviewed that the titer value at 1-3 years is indicative of long-term titer

levels. A titer check and booster if titer is under cut-off at 1-3 years will ensure long-term

immunogenicity and provide that extra level of certainty. Additionally, since the titer level has 

been raised to ≥0.5 IU/mL, this option will ensure high titers. The WG also wanted to make sure 

that a booster can be given as an option instead of a titer check, given the realization that some 

people will prefer a booster dose rather than waiting for a titer check and then potentially having 

to wait additional time to get a booster anyway. The booster can be given as soon as Day 21 

and as late as Year 3, given the current scheduling of the 3-dose PrEP series. The evidence 

table for duration of immunogenicity has a certainly of Level 3.

In summary, the WG reviewed the primary immunogenicity of rabies vaccine in children. There 

was no difference between primary immunogenicity in children compared to adults, including for 

young children, for any given schedule. For the specific schedule proposed to the ACIP, the WG 

had data from one observational study that involved the proposed PrEP series and US rabies 

vaccine. That study showed that 100% of the children aged 5 to 13 years of age mounted titers 

over the ≥0.5 IU/mL cut-off after the primary series. Regarding long-term immunogenicity, 

several of the same studies that the WG evaluated to understand rabies vaccine in children 

showed that titers in children may stay higher for longer. Since boostability is not a concern for 

adults, the WG concluded that it would not be a concern for children.

The implications of not aligning the recommendations for children and adults was discussed by

the WG. The thought was that ACIP recommendations for PrEP have always been the same for 

children and adults. If this new precedent is set, adult travelers may get a 2-dose [0, 7 days] IM 

series before travel. Child travelers belonging to the same family may not have enough time for 

the 3-dose series and may not get vaccinated at all. The end result would be that adults will 

have received PrEP and children will not have received PrEP, even though the children are the 

population at higher risk. Therefore, the WG proposed the same two recommendations to the 

ACIP that were voted on and passed during the February 2021 ACIP meeting, but for persons

under 18 years of age as shown here:

1. ACIP recommends a 2-dose [0, 7 days] intramuscular rabies vaccine series in 

immunocompetent persons <18 years of age for whom rabies vaccine pre-exposure 

prophylaxis (PrEP) is indicated.

2. ACIP recommends an intramuscular booster dose of rabies vaccine, as an alternative to 

a titer check, for immunocompetent persons <18 years of age who have sustained an 

elevated risk for only recognized rabies exposures (i.e., those in risk category #3 of 

rabies PrEP recommendations table). The booster dose should be administered no 

sooner than day 21 but no later than 3 years after the 2-dose PrEP series.
ACIP Meeting Summary May 5, 2021

9

Summary of Discussion

• ACIP requested a breakdown of the number of children under 2 years of age who were 

included in the 12 studies reviewed by the WG. Dr. Rao indicated that the exact number 

could be calculated for the June 2021 ACIP meeting.

• Dr. Kimberlin (AAP Redbook) thanked CDC and the WG for a much more robust 

presentation about what is known of use of rabies vaccines in children. He recalled raising a 

personal concern during the February 2021 ACIP meeting. He emphasized that this could 

be considered a flexible 3-dose schedule such that the booster can be given as soon as 21 

Days following the primary PrEP series of the 2 doses, assuming this is extended down to 

children. This made him more comfortable compared with the issues he personally raised 

previously. He expressed gratitude for the thorough assessment and concise presentation 

made between last time and this session.

• On behalf of the American Academy of Pediatrics (AAP), Dr. Maldonado expressed 

appreciation to the ACIP and the investigators for addressing the concerns and questions 

the AAP’s Committee on Infectious Diseases (COID) had, and for the added information.

The COID had a robust discussion during their recent committee meeting and felt 

comfortable with the data as presented. The COID raised the same issues around advising 

its pediatric providers regarding these new recommendations so that they are clear on the 

pediatric traveler.

Background and Approach to Rabies PEP

Dr. Rao (CAPT, USPHS; Co-Lead Rabies ACIP WG; CDC/NCEZID) next presented the 

components of rabies PEP, summarized the role of rabies epidemiology in decisions about 

PEP, and described a proposed approach to PEP for clinicians. For persons who have not 

previously received PEP or PrEP, PEP in response to an exposure involves RIG and 1 dose of 

vaccine soon after the exposure, which is referred to as “Day 0.” To complete the series, the 

patient receives 3 more doses of vaccine on Days 3, 7, and 14. A previously vaccinated person 

is defined in the 2008 ACIP recommendations as a person who received either: 1) one of the 

recommended PrEP regimens of human diploid cell vaccine (HDCV), purified chick embryo cell 

vaccine (PCECV), or rabies vaccine adsorbed (RVA)—all of which are cell culture vaccines 

known to be safe and efficacious; 2) one of the recommended PEP regimens of HDCV, PCECV, 

or RVA; or 3) another vaccine and had a documented rabies virus neutralizing antibody titer 

afterward. The implications of being previously vaccinated on PEP management is that it

eliminates the need RIG entirely and decreases the number of PEP vaccine doses. Someone 

who is considered previously vaccinated needs only to receive 2 doses of rabies vaccine given 

on Day 0 and Day 3. RIG is not indicated and the number of vaccine doses shortens from 4 

doses to 2 doses and is completed sooner.

There are a lot of complexities that go into who should receive PEP. The challenges of 

determining who should receive PEP is perhaps best illustrated by the large amount of PEP that 

is used in the US to prevent human rabies, with approximately 55,000 people receiving PEP 

each year in the US. The impacts of this are unnecessary administration of vaccines, the high 

costs associated with these vaccines and with rabies immune globulin in particular, emotional 

distress involved in a patient believing that they have been exposed to a high mortality illness 

and need to receive these vaccines in order to prevent death, and less availability to persons

who need it during vaccine shortage events. There are just 2 papers that describe inappropriate 
ACIP Meeting Summary May 5, 2021

10

and appropriate administration of PEP in the US.16,

17 They both evaluated whether the ACIP 

recommendations were followed and found that PEP was sometimes inappropriately 

administered. The Moran et al paper published in 2000 was a prospective case series study of 

patients presenting with an animal exposure related complaints from July 1996-September 1998

at 11 university-affiliated urban emergency departments (EDs) as part of the EMERGEncy ID 

NET. The authors found that 40% of cases of PEP administration were inappropriate, owing 

often to factors associated with an incorrect understanding of the role of rabies epidemiology

and clinician decisions about PEP. The Moran et al study also found that in 6% of cases, PEP 

was inappropriately withheld due to misunderstandings about circumstances for which PEP 

should be administered. Recognizing that it can be confusing for clinicians to know which 

exposures were at PEP, Dr. Hunter suggested during a previous ACIP meeting over a year and 

a half ago that the WG consider outlining these considerations in the updated ACIP

recommendations. The remainder of this presentation was the WG’s effort to outline these 

considerations.

To do so, an understanding of rabies epidemiology was first presented to explain some of the 

fundamentals. Human rabies is transmitted from infected mammals by a bite, scratch, or 

contamination of mucous membranes or an open wound with saliva or neural tissue. It is not 

transmitted by exposures to blood, urine, or feces. Exposures to those should not warrant PEP. 

There have been some rare cases after organ and tissue transplants, but the remainder of this

presentation focused on rabies after animal exposures. Few animal species are reservoirs for 

rabies (i.e., few species can sustain the circulation of rabies). Rabies virus variants (RVV) are 

named for the animal reservoir species in which their circulation is sustained, and RVVs are 

confined to geographically definable regions. However, it is important to understand that 

infection can be transmitted from the reservoir species to any other mammal and may not stay 

within the reservoir species. For example, the raccoon RVV can spread from a raccoon to a cat

and then to a human. This specific RVV does not denote the animal to which the human was 

exposed, but rather the reservoir for that specific variant.

To illustrate host shift and effects on rabies epidemiology, raccoon RVV on the East Coast of 

the US spread to various unvaccinated animals through bites in 2014-2015. The rate of the 

raccoon RVV in Florida spread within this species. The variant circulated among raccoons and 

then built up in this highly susceptible host population such that it was transmitted to individual 

mammals in more resistant host populations of unvaccinated dogs, foxes, or skunks exposed to 

a raccoon through a bite. Host shift events can also occur with rabies. Cross species 

transmission occurs, sometimes all over the world, but nearly every time the virus dies out in the 

non-reservoir host. Occasionally, the virus gains foothold. Sometimes this is because the virus 

mutates and adapts to the new host and sometimes it is because the virus gets lucky and finds 

a host that is genetically primed for viral circulation. When this happens, it is referred to as a 

“host shift event.”

16 Steinberg HD, Bemis K, Frias MM, Christiansen D. Inappropriate Administration of Rabies Postexposure Prophylaxis, Cook 

County, Illinois, USA. Emerg Infect Dis. 2020 Oct;26(10):2515-2517. doi: 10.3201/eid2610.200232. PMID: 32946729; PMCID: 

PMC7510732.

17 Moran GJ, Talan DA, Mower W, Newdow M, Ong S, Nakase JY, Pinner RW, Childs JE. Appropriateness of rabies postexposure 

prophylaxis treatment for animal exposures. Emergency ID Net Study Group. JAMA. 2000 Aug 23-30;284(8):1001-7. doi: 

10.1001/jama.284.8.1001. PMID: 10944646.
ACIP Meeting Summary May 5, 2021

11

While it is hypothetical that a host shift event could occur from raccoons to skunks, it is of 

concern. The last time there was a host shift event was in the 1950s in Florida when a bat 

rabies virus shifted into the raccoon population, which is the reason there is raccoon RVV on the 

East Coast. This spread from Southern Florida into Canada and created what today is called the 

raccoon rabies variant and reservoir area. It is estimated that 75% of human and pet rabies

exposures occur in this area largely due to the interactions with animals infected with this viral 

variant. This illustrates why it is very important to understand the epidemiology. This map 

illustrates the different RVVs and geographic regions of the US:

Raccoon RVV in the Eastern part of the US is a result of the post-shift from bats. There are 3

skunk RVV delineated in brown, orange, and blue as a result of host shifts from dogs or bats.

There are mongoose and fox RVV as well. This illustrates that mammal reservoirs vary by 

geography. Terrestrial (wildlife) rabies is due to the RVV for which wildlife are the reservoir.

Non-terrestrial rabies is the RVV for which bats are the only reservoir. Terrestrial rabies is 

restricted to the regions colored on this map. Non-terrestrial rabies is in all US states except 

Hawaii, which is free of all rabies. An understanding of the biogeography of rabies is essential to 

clinical decisions about whether a specific exposure warrants rabies PEP. For example, a bite 

from a raccoon in Washington State may be managed differently from a raccoon bite in 

Pennsylvania. One region has only non-terrestrial rabies and the other has a lot of raccoon 

RVV.

Fortunately, despite inappropriate PEP use in the US, there still are relatively few cases of 

rabies in humans for the time period of 2009-2020. There were 25 human cases of rabies 

among persons in the US, of which 17 occurred due to domestic exposures and 8 occurred from 

international exposures. Among the 17 domestic exposures, 12 were bat RVV, 3 were raccoon 

RVV (including kidney donor and recipient), 1 was mongoose RVV, and 1 was unknown RVV. 

Of the 8 international, 7 were due to dogs (Philippines, Guatemala, Brazil, Afghanistan, Haiti, 

India) and 1 was bat RVV (Mexico). A rabid dog has not been a source of human rabies after 

domestic exposure for a very long time because canine rabies has been eliminated in the US.

None have been due to occupational exposures or in people who received PrEP or PEP during 

the time period 2009 to 2020.
ACIP Meeting Summary May 5, 2021

12

Differing epidemiology in the 50 US states is one of the reasons that drafting a one-size-fits-all

PEP algorithm is challenging. Concern for an exposure in a terrestrial rabies region differs from 

that in a non-terrestrial rabies region, and rabies vectors and RVV differ by region. In addition, 

health departments in different regions of the country have differing management styles for 

these exposures. For example, health departments can differ in recommendations about PEP 

after an exposure in regions without Fox RVV. As another example, many (but not all) health 

departments advise against PEP for exposures to squirrels, chipmunks, and mice. Given that 

some regions have had occurrence of rabid squirrels, a general national algorithm advising 

against PEP after section exposure would be too simplistic.

The differences in health department guidance are impacted by the degree of oversight and 

case management of animal bite investigations. Guidance on health department websites can 

vary as well. Some health department sites provide detailed and complex algorithms

recommending or not recommending PEP depending on various characteristics of the 

exposure, while others provide limited online guidance and recommend consulting the health

department for case-by-case advice. The comprehensiveness of online guidance also can differ. 

Some of them omit guidance about caged rabbits, hamsters, and other so-called “pocket pets.” 

Others provide a very long list of animals that could be risky. Since health departments are an 

incredible resource and a huge source of thorough details about the local biogeography,

creating a national algorithm would overstep and result in confusion since some health 

departments provide more information than others on their websites. Those that do not provide 

information on their websites expect one-on-one consultation.

Beyond rabies epidemiology, there are other issues considered by health departments when 

advising against PEP. The WG took those into consideration in addition to the expertise that the 

health departments have about local rabies, biogeography, and the benefits of a general

framework so that clinicians could understand what factors should be considered before giving 

PEP in an attempt to balance the two. The WG tried to balance providing some sort of general 

framework for the clinician so that they realized what factors were important, but also not 

providing too prescriptive a guidance since there are a lot of nuances that go into a decision

about whether someone should receive PEP.

In terms of a general approach to PEP, the WG’s objective was to enable clinicians to handle 

“easy” cases quickly, with no need to contact the health department. The approach is intended 

to defer to the health department for guidance for the most definitive answers. Consultations 

with health department are known to decrease the odds of inappropriate PEP administration by

87%.18 Therefore, taking that away would not be good. The WG also wanted to outline the 

multiple considerations needed for decisions about PEP depending upon the exposure type.

Clinicians should be able to collect the important history before the health department

consultation to understand the factors that weigh into the decision, participate in the decisionmaking, and be better able to counsel affected patients.

The 2008 ACIP recommendations considerations when making a decision about whether to 

give PEP, including: 1) whether it was a bite or non-bite exposure, the type of animal to which 

the exposure occurred (bat, domestic dog, cat, ferret) or wild animals; 2) local animal rabies 

epidemiology; and 3) the circumstances of the biting incident in terms of whether it was 

provoked or not provoked, the behavior of the animal, and the vaccination status of the 

exposing animal. Table 3 in the 2000 ACIP recommendations details animal types, evaluation 

18 Steinberg HD, Bemis K, Frias MM, Christiansen D. Inappropriate administration of rabies postexposure prophylaxis, Cook County, 

Illinois, USA. Emerg Infect Dis.202 Oct; 26 (10): 2515-2517
ACIP Meeting Summary May 5, 2021

13

and disposition of the animal, and the PEP recommendations. Taking all of that into

consideration (health department consultation, local biogeography, clinician understanding), the 

WG drafted the following algorithm that Dr. Rao walked through step-by-step:

Exposures outside of the 50 US states are more challenging. There are approximately 30 

known reservoirs for rabies worldwide, including mongoose, dog in a canine rabies endemic

region, bats outside of the US, monkeys, and exotic animals (Australian Dassie). Given that it is 

very difficult to develop any kind of algorithm for these cases, the WG concluded that the

general guidance should be to consult the health department for case-specific advice and to 

collect information about the type of exposure, whether an exposure was provoked or not 

provoked, and the behavior of the animal and take those cases directly to the health department

for case-by-case consultation.

In summary, the WG determined that deciding which human exposure necessitates PEP can be

very challenging. The health department has a critical role in the US and consultation is 

available, including during off hours for consultation about complex cases. They really are the 

experts in local biogeography and also are the ones who can facilitate laboratory testing and 

animal observations if needed. At the same time, based on feedback the WG received from 

previous ACIP meetings and from some clinicians, some sort of framework or general algorithm 

could be useful to clinicians and would not replace the nuanced advice from public health 

veterinarians that is listed on their websites or that may be obtained through one-on-one 

consultations. The WG was somewhat split about whether the proposed algorithm would be 

helpful, but thought it might be of some benefit to provide this general guidance and request

input from the ACIP.
ACIP Meeting Summary May 5, 2021

14

Summary of Discussion

• Some ACIP members were much less worried about overuse of prophylaxis than underuse. 

Whatever diagram, chart, or recommendation ACIP puts forth should err on the side of 

caution since this is a fatal disease and it is preventable. While it is okay to test the animal, if 

someone cannot be reached for 48 to 72 hours, it should be clear that it is okay to start 

prophylaxis and then perhaps stop it if it turns out not to be appropriate.

• The algorithm could be helpful in that some patients/clinicians may not know that local 

biogeography is important in deciding whether to administer PEP or that they should consult 

with the local health department. The algorithm, review of the health department website, 

and potentially a consult with the health department could arm the clinician with enough 

information to make decisions for the patient sitting in front of them.

• Some concern was expressed that in certain circumstances, the algorithm may complicate 

rather than simplify the guidance. For instance, there has not been any evidence of 

transmission from squirrels on the West Coast so the risk is extraordinarily low. Yet, the 

algorithm could give the impression that clinicians/health departments should be thinking 

through every squirrel, mouse, or wild rodent bite. They certainly do not want the algorithm 

to create unintended consequences in which health departments are inappropriately 

consulted for every squirrel bite.

• Physicians/clinicians liked the algorithm and thought that it would be useful, but suggested 

that it needed to be more nuanced. While some thought it seemed somewhat complex as a 

rabies decision support tool, rabies consultations are probably one of the most common 

consultations that state and local health departments get and CDC also receives a lot of 

calls:

➢ Given that some of these questions arise in the middle of the night when not 

everybody is answering phone calls, the algorithm could be very helpful to at least 

get through the night. 

➢ It would be helpful to highlight the importance of consulting the health department 

website for state-specific guidance for each of the 6 animal categories. CDC/ACIP 

certainly do not want to negate the health department’s advice, so including 

something like that for every category makes sense.

➢ Sentiment was expressed that there is a necessity/responsibility in state and local 

health departments to be able to respond in any hour of the day or night. One model 

is the Arkansas Health Department, which has a veterinarian who is specifically 

tasked with receiving these calls 24/7 for her to adjudicate the exposure.

➢ Perhaps there could be a national automated decision support tool, such as the 

poison control hotline, readily accessible for patients.

Next Steps

Dr. Rao (CAPT, USPHS; Co-Lead Rabies ACIP WG; CDC/NCEZID) recapped the WG’s next 

steps. In terms of ongoing WG discussions, there are some newly licensed RIG products since 

the 2008 ACIP recommendations were published. There is also a lot of discussion 

internationally about the location of RIG administration. The World Health Organization (WHO) 

changed their recommendations during their most recent update to limit RIG administration to 

just infiltration around the wound and to not give the remainder intramuscularly. The WG has 
ACIP Meeting Summary May 5, 2021

15

been discussing the data surrounding those issues and will present on them at the next 

meeting. The number of doses for the PEP vaccine series is constantly being evaluated. WHO

shortened the number of PEP vaccine doses from a 4-dose series to a 3-dose series. The WG 

is aware that the considerations for ACIP will be different and that there will need to be a lot of 

robust data to confirm long-term immunogenicity since PEP is used as the equivalent of PrEP

for any subsequent exposure and would need to be boostable if given years previous to an 

exposure so that the patient could only get a 2-dose vaccine series. The WG is evaluating the 

available data in order to present the WG interpretation to the ACIP during the next meeting.

There are also numerous clinical guidance topics under discussion, some of which need

modification/updates of wording or phrasing in the ACIP recommendations. Topics include PrEP 

and PEP schedule deviations; PEP initiated abroad (e.g., administered intradermally, with 

vaccine unavailable in US, or according to schedule not outlined by ACIP); excessive RIG use; 

and theoretical concerns about administering PEP in a patient with rabies symptoms. The WG 

has been discussing the plan for implementation of updates. They realize that clear messaging

must be drafted for the updated recommendations. There are many stakeholder questions, so 

discussions have begun about how to engage with stakeholders (e.g., professional societies, 

public health veterinarians, travel medicine providers) to ensure that implementation strategies

are in place and revisions are clear. The CDC rabies website needs to be updated with clear 

guidance, and consultation support will need to be provided to clinicians and health departments 

when recommendations are published.

During the June 2021 ACIP meeting, the WG plans to present the proposed votes on the two 

PrEP questions for children; the WG’s interpretation of data on RIG and PEP schedules 

(GRADE and EtR if WG proposes change); and clinical guidance issues identified as frequently 

asked of health departments and CDC, which could be clearer in the ACIP recommendations.

Public Comments

The floor was opened for public comment during the May 5, 2021 ACIP meeting at 1:00 PM ET. 

Given that many more individuals registered to make oral public comments than could be 

accommodated during this meeting, selection was made randomly via a lottery. The comments 

made during the meeting are included here. Members of the public also were invited to submit 

written public comments to ACIP through the Federal eRulemaking Portal under Docket No. 

CDC–2021–0025. Visit http://www.regulations.gov for access to the docket or to submit 

comments or read background documents and comments received. 

Peter Sears, MD

Premise Health

Yes, thank you for having me. I’m a board-certified family physician and been in practice for 

about three years. And first off, I just want to thank the committee for having me and also thank 

you for your [inaudible], which has greatly contributed to the US having an extremely safe 

vaccine supply. So, thank you for your tireless effort. I want to discuss, as you all know, the FDA 

is set to approve the Pfizer SARS-CoV-2 vaccine hopefully early next week. I just wanted to sort

of encourage all my fellow colleagues in pediatrics and family medicine who work with kids of 

what the critical role children in this population are going to play in achieving herd immunity and 

how important it is for us to communicate that to the parents of our children. And keep in mind, 

children under 15 make up approximately 20% of the general population in the United States 

and it’s going to play a critical role, we as clinicians, in helping to achieve herd immunity in the 

fight against SARS-CoV-2. And as well, I think it’s really important that we stay abreast and up-
ACIP Meeting Summary May 5, 2021

16

to-date on things out there and in the social media about concern the parents have about longterm effects, infertility effects, DNA changing, all the things [inaudible]. We need to be able to 

discuss and address these concerns with our parents in a thoughtful and encouraging fashion

and be able to alleviate their concerns as to why these are not issues that they need to be

concerned about, but in a way that is understanding toward the parents and empathetic of their 

concerns. And just wanted to again just encourage us all to know what a critical role we’re going

to play amongst this pediatric population, as well as adults, as well as the general population as 

well, of course. And finally, I just also wanted to address the issue of concerns of falling behind 

on the routine schedule during this pandemic just to remind how important it is for us all to

remain vigilant that our patients don’t fall behind on the CDC recommended schedule. But 

again, once again, thank you so much for allowing me to comment and I will leave it at that.

Sarah Barry

Concerned Citizen

Independent Pro-Vaccine Advocate

Hello, my name is Sarah Berry. I am an independent pro-vaccine advocate and online I go by 

the name “42believer.” In my first public comment, I talked about how anti-vax lobbyists

attempted to censor my testimony. In my second, I began to touch on the rampant abuse of

autistic children within the anti-vaccine community. At the risk of sounding like a broken record, I 

must return to that awful subject as I inform you all about MMS. MMS stands for Miracle Mineral 

Solution and has long-been touted as a cure-all by a cult known as the Genesis II Church of 

Health and Healing. Unfortunately, MMS is in fact a type of bleach and is very dangerous for

consumption, obviously. The leaders of the cult were finally arrested after claiming that MMS

could cure COVID-19, but unfortunately for hundreds of autistic children, that arrest came far 

too late. It was through the efforts of Kerri Rivera that the book “Healing the Symptoms Known

As Autism” was published, giving a detailed guide on how to administer MMS orally, topically, 

and rectally for the purposes of healing/curing autism. It was through my efforts that I was able 

to get that book “Healing the Symptoms Known As Autism” banned from sale from Amazon 

back in 2019. It is disturbing to know that this book was for sale at all—that anti-vaxxers seem 

to not even notice that such a horrible cure could be touted within their community. I have seen 

Kerri Rivera present several years at a very well-known autism anti-vax convention called

AutismOne. Even after Kerri Rivera was banned from the State of Illinois by the Attorney 

General from promoting MMS, AutismOne still brought her back to speak virtually, kind of 

getting around the rules so to speak, because even though MMS is bleach and that is an 

absolute fact, people in the anti-vax community are unwilling to grapple with this concept that 

this is abuse. I have actually had to contact Children’s Services multiple times because I truly 

believe it’s a fact that giving MMS to an autistic child or an autistic adult is abuse. It’s medical 

abuse. It’s neglect you could even say. And unfortunately, all three of those instances where I 

reported the caregiver, none of those ever resulted in action or removal of the autistic child from 

that home. So again, I just need to stress that this is a very large part of the anti-vaccine 

community. It is easier to convince people that anti-vaxxers are wrong if you talk about the side

of the community. Until anti-vaxxers grapple with this disconnect, I’m going to continue talking 

about this problem. Thank you.
ACIP Meeting Summary May 5, 2021

17

DENGUE VACCINES

Introduction

Dr. Wilbur Chen (ACIP, WG Co-Chair) provided an introduction to the Dengue Vaccines 

session, extending gratitude to the ACIP members and other members and consultants who 

have been seminal in the WG’s discussions. He noted that for Dengvaxia®(CYD-TDV), the 

pivotal licensure efficacy data were generated in 2015. This resulted in the WHO’s Strategic 

Advisory Group of Experts (SAGE) making the initial recommendation for the use of this vaccine 

in May 2016 among individuals 9-45 years of age in high prevalence areas. In 2017, there was 

disclosure of new information about this vaccine from a case-cohort study showing increased 

risk of severe dengue among persons who are seronegative prior to vaccination and then have 

subsequent infection. In April 2018, SAGE revised their recommendations to state that a prevaccination screening strategy must be formulated so that only dengue seropositive persons 

would be vaccinated. In May 2019, the US Food and Drug Administration (FDA) licensed this 

vaccine.

As a reminder, ACIP’s Dengue Epi and Vaccine Development WG was formed in 2017 and was 

put on hold in 2018 when the Flavivirus WG split and the Dengue WG was formed. In 2019, 

there was extensive discussion regarding Phase 3 results, safety and pharmacovigilance,

GRADE, cost-effectiveness, dengue diagnostics, partially effective vaccines, dengue vaccines

in the Philippines, Vaccine and Related Blood Products Advisory Committee (VRBPAC) review,

and FDA approval. In 2020, the focus was on vaccine acceptability, WHO’s global position, 

feasibility, and health equity. In 2021, the focus has been on dengue immunoglobulin G (IgG)

test evaluation, the EtR Framework, and draft recommendations presented to ACIP. Between 

February and May 2021, the Dengue Vaccine WG group has discussed performance 

recommendations for a pre-vaccination screening test, the EtR Framework, and key messages 

for providers and families.

During the February 24-25, 2021 ACIP meeting, the importance of a specific test for prevaccination was discussed. To recap, CYD-TCV vaccine requires pre-vaccination screening. 

Pre-vaccination dengue screening needs to be specific to minimize vaccination of seronegative 

children and sensitive to maximize identification of children who can benefit, and test 

performance characteristics to be included with ACIP recommendations. A CDC evaluation 

identified 1 enzyme-linked immunosorbent assay (ELISA) test and 2 rapid tests meeting 

recommended criteria with high specificity and sensitivity. The plan for the May 2021 meeting 

was for the WG to present the EtR Framework and draft WG recommendations to ACIP, with no 

vote planned on Dengvaxia®(CYD-TDV) recommendations until the June 2021 ACIP meeting.

Dengue Vaccine EtR Framework

Dr. Gabriela Paz-Bailey (CDC/NCEZID) reminded everyone that dengue virus (DENV) is 

transmitted by species of mosquitoes, especially Aedes aegypti and Aedes albopictus. This as 

the most important arbovirus in terms of worldwide morbidity and mortality, with an estimated 

400 million infections every year. Dengue fever can range from asymptomatic or mild to severe

disease, and mortality range can go from 0.2% if treated to as high as 20% if untreated. The 

causes of death are mainly unrecognized or prolonged shock, unrecognized hemorrhage, fluid 

overload, and nosocomial sepsis. The first infection with dengue is usually mild and will induce 

antibodies against the 3 other dengue viruses for a period of time. However, the antibody levels 
ACIP Meeting Summary May 5, 2021

18

decrease over time and then suddenly go from being protective against future infections to

being harmful in a process known as antibody-dependent enhancement (ADE).

19 The theory is

that there are not enough antibodies to effectively neutralize the virus, but there are enough to 

bind the virus and help it enter into immune cells and then activate all types of inflammatory 

responses. This explains why the second infection is proven to be the most likely to lead to 

severe disease.

20 It also explains why making a dengue vaccine has been so difficult. If 

someone does not have immunity to all 4 virus types, there is a possibility that they may have

low levels of antibodies that can lead to ADE.

The Phase 3 trials included children 2 to 16 years of age in countries in Asia and Latin America.

When the results were published in 2015, there was a safety signal of increased risk of

hospitalization and severe disease among children 2 to 5 years of age. Because of that, the

vaccine was recommended by the WHO for persons 9 years of age and older in highly endemic 

areas. It was first licensed in several countries, including the Philippines. In 2016, the

Philippines started giving it to all children 9 to 10 years of age. After additional testing of 

specimens from the trial participants and further analysis, Sanofi eventually found that the 

increased risk of severe disease and hospitalization among vaccinated seronegative children 

compared to controls. If the vaccine is given to a child who has not been infected previously, it 

works as a silent primary infection that does not fully protect against all serotypes. When the 

child gets naturally infected through a mosquito bite, they get the second infection that is the 

riskiest for severe dengue. If the vaccine is given to a child who had dengue before, this skips

the second infection and the next natural infection they get is like a third or fourth infection.

After this information was released from Sanofi, the WHO revised their recommendation to state 

that the vaccine should only be given to children with laboratory-confirmed evidence of past

infection. Unfortunately, the Philippines had already vaccinated almost 1 million children without 

doing any testing and the backlash was huge. The suspension of the program broke public trust

in the dengue vaccine and in vaccines in general. The hospitalized severe cases that occurred 

following vaccination were a mixture of breakthrough cases among those who were seropositive

and cases among those who were seronegative when vaccinated. Later analysis of the data in 

the Philippines has suggested that most dengue hospitalizations among vaccinated children

were actually breakthrough disease. A small percentage were vaccine-induced hospitalizations.

The most important take-home message is that in the case of the Philippines, there was no

screening before vaccination. The available data have shown that this is a safe and effective

vaccine for children 9 to 16 years of age with evidence of a past dengue infection.

The FDA licensed this vaccine in 2019 for this group of children who live in an endemic area in 

the US. However, there were no commercially available serological tests at that time that 

reliably determined whether a child had a past dengue infection. In order to determine if safe 

implementation of the vaccine was feasible, CDC evaluated commercially available tests to 

detect dengue antibodies. This evaluation confirmed that there are tests available with high

specificity and adequate sensitivity. The Dengue Vaccine WG drafted recommendations on the 

performance of tests used for pre-vaccination screening that include a minimum specificity of

98% and a sensitivity of 75%.

19 Whitehead SS, Blaney JE, Durbin AP, Murphy BR. Prospects for a dengue virus vaccine. AP, Murphy BR. Prospects for a dengue 

virus vaccine. Nat Rev Microbiol. 2007;5(7):518‐528. oi:10.1038/nrmicro1690

20 Flasche S, Jit M, Rodríguez‐Barraquer I, et al. The Long‐Term Safety, Public Health Impact, and Cost‐Effectiveness of Routine 

Vaccination with a Recombinant, Live‐Attenuated Dengue Vaccine (Dengvaxia): A Model Comparison Study. von Seidlein L, ed. 

PLoS Med. 2016;13(11):e1002181. doi:10.1371/journal.pmed.100218
ACIP Meeting Summary May 5, 2021

19

The WG assessed each of the elements in the traditional ETR Framework for the policy 

question, “Should 3‐doses of Dengvaxia® be administered routinely to persons 9‐16 years of 

age with laboratory‐confirmed previous dengue infection and living in endemic areas? The 

questions for each domain were:

EtR Domain Question

Public Health Problem • Is the problem (Dengue) of public health importance?

Benefits and Harms • How substantial are the desirable anticipated effects of the intervention 

(dengue vaccine)?

• How substantial are the undesirable anticipated effects?

• Do the desirable effects outweigh the undesirable effects?

Values • Does the target population feel the desirable effects are large relative to the 

undesirable effects?

• Is there important variability in how patients value the outcomes?

Acceptability • Is the intervention acceptable to key stakeholders?

Feasibility • Is the intervention feasible to implement?

Resource Use • Is the intervention a reasonable and effective allocation of resources?

Equity • What would be the impact of the intervention on health equity?

In terms of the first question in the EtR Framework regarding whether dengue disease is of 

public health importance, 90% of the population at risk for locally-acquired dengue resides in 

Puerto Rico (PR). Other territories that are considered endemic or affiliated states include 

American Samoa, the US Virgin Islands (USVI), the Federated States of Micronesia (FSM), 

Palau, and more recently, the Marshall Islands. Dengue epidemics occur in a cyclical pattern 

every 5 or so years, with 95% of dengue cases in the US territories occurring in PR. There has 

been an unusually long period with little dengue transmission in PR since 2014. However, 

dengue cases started being reported again in 2020. Over 1,000 polymerase chain reaction 

(PCR)-confirmed cases have been reported since the beginning of 2020.

Looking at dengue virus cases and hospitalizations by age in PR from 2010-2020, most dengue 

cases and the highest incidence occurred in children 10 to 19 years of age. There is a similar 

pattern for dengue hospitalizations. In contrast, 88% of deaths occurred in adults. Nearly 90% of 

cases occurred among adults ≥20 years old. Prevalence data among children are available only 

from PR and not from other US territories. In 2017, seropositivity was estimated at 50%.21 There

also are data from the Phase 3 trials that Sanofi conducted that suggested that 56% of the 

children ages 9 to 16 years were seropositive.22 More recently, CDC found similar results from a 

survey conducted in 2018 among children in Southern PR, with nearly 60% seropositive among 

children 9 to 16 and seroprevalence at 9 years of age being 50%.23 The WG concluded that 

dengue is a disease of public health importance.

With respect to benefits and harms and the question regarding how substantial the desirable 

anticipated effects are, survey results from Asia and Latin American show a combined efficacy

against virologically confirmed dengue (VCD) among seropositive participants 9 to 16 years of 

age of about 82%.24 Efficacy varies by serotypes and is higher for serotype 4 at 89%. Efficacy 

was lower for serotypes 1 and 2 at 67% and 80% for serotype 3. Efficacy against 

hospitalizations and severe dengue was estimated as far as the case-cohort study with three

different methods (multiple imputation, TMLE, and NS1 testing). Based on the multiple 

21 Argüello DF, et al. AJTMH. 2015 Mar 4;92(3):486‐91

22 L’Azou M, et al. TRSTMH. 2018 Apr 1;112(4):158‐68

23 Unpublished: COPA Project

24 Hadinegoro SR et al. N Engl J Med 2015;373:1195‐1206
ACIP Meeting Summary May 5, 2021

20

imputation results, there was a 79% reduction in hospitalization risk and an 84% reduction in the 

risk of severe dengue (estimated as one minus the relative risk).25 The WG considered the 

desirable anticipated effects to be moderate to large.

With regard to the undesirable effects, the most important one is increasing the risk of

hospitalization and severe dengue by erroneously vaccinating a seronegative child. The point

estimate for the relative risk is greater than 1.0, suggesting an increased risk of these outcomes 

when vaccinating seronegative children ages 9 to 16 years. The increased risk in seronegative 

vaccinees compared to controls for hospitalizations was between 40% to 50% greater risk, and 

for severe dengue between 2 to 6 times as high as in the controls. The differences were not 

statistically significant because of the small sample size of seronegatives in the trial.25 For 

severe adverse events (SAEs) and deaths, there were no differences for SAEs at 28 days. At 6

months, there were fewer SAEs among vaccinees compared to controls. There were no

differences in deaths.26 The WG considered the undesirable effects to be small.

Regarding whether the desirable effects outweigh the undesirable anticipated effects, the 

benefits of Dengvaxia® are that it prevents symptomatic dengue hospitalizations and deaths 

among seropositive children. The efficacy against symptomatic dengue is 82%, against 

hospitalization 79%, and against severe dengue 84%. The main potential harm is increased risk

of vaccine-induced hospitalization and severe disease when a seronegative child is vaccinated

after a false-positive laboratory test result.

To assess the issue of the balance between benefits and harms, researchers from the 

University of Notre Dame27 conducted an agent-based model (ABM) of dengue transmission 

with humans and mosquitoes represented as agents. The model was calibrated to simulate 

dengue transmission in PR. It compared pre-vaccination screening and subsequent vaccination

of seropositive 9-year-olds to the status quo. The model population was 9-year-olds, with a new

cohort of 9-year-olds being vaccinated every year. They were followed for 10 years keeping

track of dengue infections, hospitalizations, and deaths. Dr. Paz-Bailey reported results on two 

scenarios of 50% seroprevalence and 30% seroprevalence. The population level benefits were 

symptomatic and hospitalized cases averted and the risks were vaccine-induced 

hospitalizations among seronegative individuals. Using a test with a 75% sensitivity and 98% 

specificity, the model estimated baseline symptomatic and hospitalized cases among the entire 

population. Among children 9 to 16 years of age, the model estimated the number tested and 

vaccinated, symptomatic cases and hospitalizations averted, and the number of additional 

hospitalizations by erroneously vaccinating seronegatives with a false-positive test result.

In this scenario of 50% seroprevalence, more than 4,000 symptomatic dengue cases nearly 

3,000 hospitalizations would be averted annually. There would be 51 vaccine-induced 

hospitalizations among dengue-naive children or seronegative vaccinated after a false-positive 

result. In a lower seroprevalence scenario of 30%, over 1,500 symptomatic dengue cases and 

over 1,200 hospitalizations would be averted. There would be 112 vaccine-induced

hospitalizations among seronegative children vaccinated after a false positive result. In

summary, the population risk of a screen and vaccinate strategy over 10 years in a 50%

seroprevalence scenario would be 51 vaccine-induced hospitalizations. The benefits would be 

over 4,000 fewer symptomatic cases and nearly 3,000 fewer hospitalizations. In a lower 

seroprevalence scenario, the population risk would be 122 vaccine-induced hospitalizations 

25 Sridhar, S, et al. N Engl J Med. 2018 Jul 26; 379(4):327‐340

26 Gustavo Dayan, Sanofi, personal communication

27 Espana G, Leidner A, Waterman S, Perkins A. Cost‐effectiveness of Dengue Vaccination in Puerto Rico.

https://www.medrxiv.org/content/10.1101/2020.10.07.20208512v1
ACIP Meeting Summary May 5, 2021

21

among seronegative children. The benefits would be over 1,500 fewer symptomatic cases and 

over 1,200 hospitalizations prevented. The WG interpretation of the benefits and harms was that 

there was a positive balance for benefits versus harm and that this balance varied by the 

seroprevalence among old 9-year-olds. The WG interpretation was that the balance favors 

intervention. The WG evaluated the certainty of the evidence following the GRADE methodology

for the outcomes of biologically confirmed dengue, hospitalizations, severe dengue, and death.

Certainty was considered high for efficacy and moderate for safety.

To answer the question of whether the target population feels that the desirable effects are large 

relative to the undesirable effects, CDC conducted a survey in Ponce, PR. This study found that 

75% of parents said that they were interested in vaccinating their children with a hypothetical 

dengue vaccine if the vaccine was provided for free, while 68% said they would be interested in 

vaccinating their children if they had to pay for the vaccine. A total of 342 out of the 1,139

participants said they were unsure or that they would not vaccinate. Among these participants, 

side effects was the number one concern. The WG interpretation was that probably yes, the

study population felt that the desirable effects were large relative to the undesirable effects.

Regarding the question about whether there is important uncertainty about viability and how 

much people value the main outcome, the WG considered that there was probably important

uncertainty or variability. To answer the question pertaining to whether the intervention is 

acceptable to stakeholders, the University of Georgia (UGA) conducted a survey among 109 

physicians in PR in 2020 and showed that 56% were familiar with the vaccine. After describing 

the need for screening before vaccination, 72% said that they would recommend the vaccine if 

there was a test with acceptable specificity. The WG interpretation was that probably yes, the 

intervention was acceptable to key stakeholders.

In terms of whether the intervention is feasible to implement, there are several considerations 

for Dengvaxia®. Implementation of vaccination for Dengvaxia® will be more challenging than for 

other vaccines as 3 doses are required at 0, 6, and 12. Extensive education of providers and 

parents will be needed. The vaccine costs will be covered by Vaccines for Children (VFC) or 

insurance, but there still will be out of pocket expenses because of the repeated visits. The 

requirement for screening before vaccination is not needed for any other vaccines. For 

screening to be conducted safely, the first step is to have tests available with good specificity.

Determining if tests were available was one of the WG’s priorities. After the CDC-led evaluation

mentioned earlier, 2 versions of the rapid test were identified and analyzed a test with high 

specificity and moderate sensitivity. Implementation of point-of-care testing in PR is challenging

since only laboratory technicians can conduct testing. None of the tests with adequate

performance have FDA approval. PR laboratories have experience implementing non-FDA

approved tests under Clinical Laboratory Improvement Amendments (CLIA) protocols and can 

provide results to participants. They have had conversations with insurance companies and 

Medicaid about covering the cost of the test, which they would do if there is a routine ACIP 

recommendation. If the recommendation is shared decision-making, they may require proof 

from providers that the test is needed before reimbursing the cost. Screening before vaccination 

will result in additional visits to the pediatrician office, laboratory, and vaccination clinics and will 

affect feasibility.

The Dengue Vaccine WG developed guidance on test performance for pre-vaccination

screening. If there is an ACIP recommendation, this guidance would be published as part of the 

MMWR that accompanies the recommendation. The guidance includes that tests should have a 

sensitivity of 35% or greater and a specificity of 98% or greater. The positive predictive value

(PPV) should be 90% or greater and the negative predictive value (NPV) should be 75% or 
ACIP Meeting Summary May 5, 2021

22

greater to minimize missing persons who would potentially benefit from the vaccine. The WG 

also considered that sequential testing using a 2-test algorithm could help improve specificity. It 

is currently challenging to think about a 2-test algorithm with the limited number of tests

available, but it may be an option in the future as more IgG tests become available. A 

communication plan will be a key component of the implementation of these vaccines, and will 

include counseling messages for providers on how to communicate the risks and benefits of 

their vaccine. Dr. Paz-Bailey shared some draft examples of these messages that they have 

been validating with a series of focus groups—first with WG members and then with dengue 

clinical experts in PR. There is a third focus group with pediatricians and general practitioners.

They are in the process of finalizing these key messages, but she wanted to show ACIP that

they have been having a lot of progress in this area. The WG interpretation was that probably 

the intervention would be feasible to implement.

Turning to the question of whether the intervention is a reasonable and efficient allocation of 

resources, Figure 5 in the cost-effectiveness modeling from University of Notre Dame shows 

here the incremental cost-effectiveness ratio (ICERs) for averted symptomatic infections and for 

averted hospitalizations. An ICER can be interpreted as the cost of the intervention minus the

cost of hospitalization and treatment for each quality-adjusted life-year (QALY) gained or for 

each symptomatic case or hospitalization averted. A lower ICER indicates a more cost-effective 

vaccine. The ICER goes up with lower seroprevalence and a higher cost of the vaccine. At a 

seroprevalence of 50% at age 9 and an estimated cost of the 3 doses of the vaccine of $382,

the ICER is estimated to be 122,000 per QALY gained for the 50% seroprevalence scenario and 

240,000 per QALY gained for the 30% seroprevalence scenario.28 To put this ICER into context, 

Dr. Paz-Bailey used a graph from a review paper in Pediatrics of the ICER for other pediatric 

vaccines. Vaccines were ordered in the graph from the least cost-effective with the highest 

ICER to the most cost-effective with the lowest ICER.29 The WG’s judgment was between 

probably yes and yes that the intervention is a reasonable and efficient allocation of resources.

With respect to the question regarding the potential impact on health equity, there are marked 

disparities in healthcare between PRs and other US citizens. PR has the lowest Medicaid and 

Medicare per capita annual spending. Mosquito-borne diseases are highly prevalent, and PR 

has repeatedly suffered natural disasters like hurricanes and earthquakes that affect the risk of 

vector borne diseases. The WG discussed a number of considerations to ensure that the use of 

Dengvaxia® helps reduce health inequities. First, health insurance and Medicaid should cover 

the cost of the laboratory test. The cost of the test should be minimal and funds should be 

available for those who are not covered by insurance or Medicaid. Second, multiple visits to the 

pediatrician, laboratory, and vaccination site will be challenging and maybe a larger burden for 

low-income families because of transportation costs and missed days of work. Strategies to

reduce the number of visits would be needed to reduce the impact on health equity. The WG

considered that the use of the vaccine probably would increase health equity.

In terms of the balance of consequences, the WG considered that the desirable consequences 

probably outweigh the undesirable consequences in most settings. The WG also considered 

that there was sufficient information to move forward with a recommendation.

28 Espana G, Leidner A, Waterman S, Perkins A. Cost‐effectiveness of Dengue Vaccination in Puerto Rico. 

https://www.medrxiv.org/content/10.1101/2020.10.07.20208512v1

29 Ismael R. Ortega-Sanchez et al. Pediatrics 2008; 121:S63-S78
ACIP Meeting Summary May 5, 2021

23

Summary of Discussion

• In response to an observation that parents rather than physicians are the key stakeholders, 

Dr. Paz-Bailey indicated that they have been studying who the key stakeholders are going to 

be to implement a vaccination program against dengue in PR and to implement it well. There 

are different associations of parents and different associations of physicians. They want to 

work with Tecnología Médica, other healthcare providers, municipalities, the government,

and the media. In the process of mapping all of the stakeholders, they have that clinicians are 

a very important group because they are the ones providing information to parents on the 

benefits and risks of vaccination and are the ones who the parents trust.

• Regarding an inquiry about why an adjustment was not made to the 2008 dollars used in the 

cost analysis, Dr. Paz-Bailey indicated that 2008 was the latest survey available comparing 

hospitalization costs. They have been working closely with the University of Notre Dame who 

has kindly reviewed the model to provide additional data on a higher specificity and 

sensitivity. They also could consult with them to find out whether there is an opportunity to 

update the model with more recent cost estimates.

• Concern was expressed with the lack of endemic disease since 2014 in terms of the ability to 

understand the antibody signature after vaccine in the absence of repeated infection soon 

after infection when it was more prevalent and with regard to ADE. Dr. Paz-Bailey pointed out 

that Dengvaxia® does not provide balanced protection against all 4 serotypes. It is primarily a 

vaccine against dengue 4, which is why it cannot be used among dengue-naïve individuals. It 

would need to provide protection among all serotypes to prevent the resulting effect of ADE if 

someone is vaccinated and then is naturally infected by a mosquito. It is known from studying 

dengue without the vaccine that there are cross-protective antibodies generated after a 

natural infection that last about 2 years. After 2 years, ADE begins occurring. The longer the 

separation between the first and the second infection, the more likely it can result in severe 

dengue. Based on the data provided by Sanofi on the children they have been following, 

protection against hospitalization is still present in Years 5 and 6 after vaccination and that 

protection is still effective.

• In regard to what the recommendation would be for a scenario in which someone had a prior 

infection, was vaccinated, started their vaccination series but in the midst of that series had a 

breakthrough of dengue, Sanofi said that they would still recommend completion of the 

vaccination schedule as they have shown that even 1 or 2 doses are effective.

• The epidemiology of many of the diseases that they are trying to vaccinate against change 

over time, which might change the risk/benefit calculation. The dengue circumstance seems 

even more prone to changes in risk/benefit based on changes in the epidemiology and 

seroprevalence. With that in mind, it was suggested that if this recommendation comes to a 

vote in June 2021 and the vote is favorable, perhaps the EtR should be explicitly reevaluated more formally 24 months from when the recommendation is made. Dr. Cohn 

reminded everyone that the epidemiology and ACIP recommendations are always monitored 

and reviewed. While a formal review could be done, 24 months out might not be sufficient for 

monitoring trends and assessing changes.
ACIP Meeting Summary May 5, 2021

24

• Dr. Paz-Bailey emphasized that it is important to note that with temperatures rising and 

increased travel and connectivity, the incidence of dengue has been increasing worldwide. 

An alteration of that increasing trend was observed likely because of Zika and the crossprotection it may be providing. In 2019, there were huge outbreaks in Latin America, which 

suggests that dengue continues to be a large threat. While PR was somewhat safe in 2019, 

they are now seeing increases and are expecting a large dengue outbreak during the 

mosquito season.

• ACIP members emphasized the critical importance of appropriate education/messaging, as 

well as long-term surveillance.

Draft Recommendation

Dr. Gabriela Paz-Bailey (CDC/NCEZID) reminded everyone of the policy options for ACIP, 

which are that: 1) ACIP does not recommend the intervention (intervention may be used within 

FDA licensed indications); 2) ACIP recommends the intervention for individuals based on 

shared clinical decision-making; and 3) ACIP recommends the intervention. The WG had a lot of 

discussions about the different options, so Dr. Paz-Bailey shared some of the considerations

from the WG for each option in terms of the pros and cons.

Regarding Policy Option 1 (ACIP does not recommend), the cons are that a vaccine proven to

protect persons with prior dengue infection is not going to be available to US citizens. It also 

puts off making difficult decisions that may be needed for future dengue vaccines approved by 

FDA. The pros are that this option would avoid complicated implementation in the middle of the 

COVID vaccinations program.

The WG assessed various attributes they considered important for Option 2 (ACIP recommends 

based on shared clinical decision-making) compared to Option 3 (ACIP recommends, or a 

routine recommendation). In terms of the impact of the recommendation on the reduction of 

dengue transmission, it would be unlikely for the vaccine to have an impact on dengue

transmission since it mainly reduces disease and severity of disease, but does not prevent 

infection. Regarding reduction in disease burden, the model that was presented earlier

estimated that of all dengue hospitalizations among all age groups, about 6% would be averted 

in a 10-year period with 80% coverage of the screen and vaccinate strategy and a 50% 

seroprevalence scenario. With shared decision-making, there will be no measurable benefit in 

reducing hospitalizations. In terms of harms, the balance shared earlier was that for every 57

hospitalizations prevented, 1 additional hospitalization would occur due to the vaccine. With 

shared decision-making, coverage would likely be low and among a selected group of patients.

Therefore, potentially AEs would be unlikely in terms of vaccinated seronegatives.

With regard to cost, with a routine recommendation, coverage of the screening test and the 

vaccine by insurance companies and VFC/Medicaid would be achieved and would minimize 

cost to families. In terms of shared decision-making, insurance companies were less certain 

about covering the cost of the tests without documented medical indication by a provider. While 

the vaccine would be covered, the coverage of the test was uncertain. Possibly, there would be 

higher out-of-pocket expenses for families. In terms of implementation and feasibility, with a 

routine recommendation there will be greater engagement from health departments with

territory-wide policies that would lead to greater coverage. There would likely be a greater push

to solve the information systems connectivity and testing and logistical challenges. The health 

department could centralize testing at a reference laboratory, facilitating access to testing and 

the logistics of providing results back, with phased implementation. This also would remove 
ACIP Meeting Summary May 5, 2021

25

some of the burden of testing and vaccination from providers on making those decisions. It also 

may lead to implementation of dengue vaccine programs in other countries with a high dengue 

burden. For shared decision making, it would allow for a quicker but probably limited use of the 

vaccine. In theory, it would allow for more careful discussion between providers and parents. It 

could lead to a full recommendation later after the vaccine gains are more acceptable. It does 

place the burden on providers, leading to delays and maybe missed opportunities for testing

and vaccination. This path may be a “dead end” for these vaccines and for any other 

unbalanced dengue vaccines that can still provide a benefit to a group of the population.

In terms of health equity, the WG considered that a routine recommendation would increase

health equity and that shared decision-making likely would decrease health equity since fully 

empowered and informed patients are those served by informed doctors who would have 

access to the vaccines. The administrative hurdles and the cost could reduce access for 

families with low medical literacy and economic means. For education of providers and families,

with a routine recommendation, educational materials and training for providers would be more 

readily available. For shared decision-making, there would be efforts from CDC on educating 

providers and patients. However, the WG was worried about less buy-in from the health 

department. For cost-effectiveness, a routine recommendation would achieve higher coverage.

It seems that this strategy would be cost-effective in most scenarios. With shared decisionmaking and very low coverage, it would likely not be cost-effective.

Regarding communication and media, under a routine recommendation, communication would 

fall to the health department and to CDC. Something that would need to be explained is that 

hospitalizations among children with a history of vaccinations mainly will be due to vaccine

breakthrough and a small percentage will be vaccine-induced. Clinicians and the public could 

attribute all hospitalizations to the vaccine, so a communication campaign would need to explain 

this difference. A risk is that faulty implementation could lead to negative perception of dengue 

vaccines and vaccines in general. This is a particular concern during efforts to achieve high

coverage for COVID vaccine. With shared decision-making, there will be slow implementation

and limited coverage that would make public relations issues less likely. Vaccine safety

concerns may vary by individual, so shared decision-making would lessen fears that the vaccine 

will become controversial and a stimulus to vaccine hesitancy.

To summarize Option 2 (shared decision-making) the WG considered the cons to be lower 

uptake, little progress in sorting out feasibility, coverage of tests by insurance companies more 

challenging, may lead to an increase in health inequities, and less buy-in for large education 

and communication campaigns. The pro is that it would lessen fears that the vaccine will 

become controversial and result in increased vaccine hesitancy. In summary of Option 3 

(routine recommendation), the WG identified the cons to be the perception that all 

hospitalizations among vaccinees are related to the vaccine, while most hospitalizations are 

actually due to vaccine breakthrough. There could be media backlash that could reduce

coverage for other vaccines if not managed appropriately. In terms of the pros, it is a useful 

vaccine for seropositives during a time in which sustainable vector control for Aedes aegypti is

still years off in the US while dengue outbreaks continue to occur. Greater coverage could be 

achieved and hospitalizations could be reduced. There likely would be better buy-in from health 

departments and immunization programs to resolve the challenges with feasibility. There would 

be broader communications and media campaigns, as well as an increase in health equity.
ACIP Meeting Summary May 5, 2021

26

The WG considered Policy Option 3, ACIP recommends the intervention, to be the best option 

and presented the following draft recommendation to ACIP:

ACIP recommends 3 doses of Dengvaxia® administered in persons 9-16 years of age

with laboratory confirmation of previous dengue infection and living in endemic area.

Summary of Discussion

From the consumer perspective, the health equity issue around shared clinical decision-making

is significant. In addition to concern about medical literacy, a shared clinical decision-making 

recommendation would mean that some children who are candidates would be missed because 

a provider may not raise the issue, which would be consistent potentially with CDC guidance

that it is up to the provider to raise the issue. Parents may not know what to ask. Because 

dengue is a significant public health problem and 75% of parents surveyed said they were 

interested in having their children vaccinated, a routine recommendation would be more

appropriate under these circumstances.

Asked to expand on the insurance company discussions, Dr. Paz-Bailey indicated that these 

discussions are highly preliminary. They had one meeting with representation from 4 or 5 of the 

large insurance companies to explain the details of this vaccine and how testing before 

vaccination is needed, and inquire as to whether insurance companies would be willing to 

provide coverage for that test. Their response was very positive that if the vaccine was 

recommended, they would favor preventive strategies and would cover the tests. The 

companies were specifically asked whether a recommendation for shared decision-making 

would make a difference, to which the insurance companies responded that they would have to 

meet with their boards and decide once the recommendation was made. One of the companies

mentioned that in some situations similar to this, they require documentation from the provider

that the test is indicated. This issue will be revisited once an ACIP recommendation is decided 

upon. They met with the group managing Medicaid for PR, which said they would cover the test 

if the cost was low enough. With their current work plan, they would need to submit a request for 

an amendment on the amount of funds and how the funds are spent based on the estimated 

cost of the test. The group was provided with information on the size of the population of 

children 9 to 16 years of age and the estimated cost of the test received from Sanofi of between 

$5 to $10, with a frequency of testing every 2 years. While they thought that the cost of the test 

would be covered, they still have to assess whether it could be covered under current plans and 

report back.

In response to a suggestion about providing information about specific tests in the 

recommendation and/or on the CDC website, Dr. Paz-Bailey indicated the WG discussed 

refraining from recommending particular brands and specific tests. The proposal is to include a 

paragraph in the MMWR that will accompany the recommendations that will spell out the 

minimum sensitivity and specificity. She will ask the division about the potential to provide 

general guidance for providers on the CDC website about the most recommended tests. It is 

important to remember that due to the wide range of performance of the available tests on the 

market, the testing is likely to be done in the laboratory, with the health department having more 

room to regulate. In the context of PR and their regulations about who can perform testing, this 

testing is mainly going to be performed in the reference laboratory.
ACIP Meeting Summary May 5, 2021

27

It was noted that there is a precedent for CDC recommending certain tests, which occurred in 

the 1990s when the first commercial human immunodeficiency virus (HIV) tests were coming on 

the market. Perhaps the WG could conduct a historical review of the MMWRs from the 1990s to 

find that recommendation.

While some ACIP members were leaning toward shared clinical decision-making, they were 

swayed toward making a firm recommendation due to the compelling argument about health 

literacy.

It was suggested that perhaps more consideration should be given to people who go back and 

forth between endemic countries. Some people who mainly live in the continental US and travel

to endemic areas would not be covered with the current indication. Perhaps this should be the 

next step to consider.

Dr. Maldonado (AAP) emphasized that Dengvaxia®is an important vaccination strategy for highrisk children in high-prevalence areas and that the data have been much improved over the last 

few years. However, some of her colleagues in the AAP are not comfortable with the shared 

decision-making at this point, given that there are so many unknowns (e.g., implementation, 

when screening would take place, vaccine confidence, high risk for social vulnerability, test 

development, payment/reimbursement uncertainties, et cetera). On behalf of the pediatricians in 

the community that AAP serves, she stressed that this recommendation did not seem ready for 

primetime. More details on all of these issues would be beneficial.

Suggestions for topic areas for the June 2021 ACIP meeting: implementation strategies, vaccine 

confidence, post-implementation safety monitoring, screening intervals, social vulnerability, test 

development, and payment/reimbursement.
ACIP Meeting Summary May 5, 2021

28

CERTIFICATION

Upon reviewing the foregoing version of the May 5, 2021 ACIP meeting minutes, Dr. Jose 

Romero, ACIP Chair, certified that to the best of his knowledge, they are accurate and 

complete. His original, signed certification is on file with the Management Analysis and Services 

Office (MASO) of CDC.
ACIP Meeting Summary May 5, 2021

29

ACIP MEMBERSHIP ROSTER

CHAIR

ROMERO, José R, MD, FAAP 

Arkansas Secretary of Health 

Director, Arkansas Department of Health 

Professor of Pediatrics, Pediatric Infectious Diseases 

University of Arkansas for Medical Sciences 

Little Rock, Arkansas 

Term: 10/30/2018-06/30/2021 

EXECUTIVE SECRETARY

COHN, Amanda, MD 

Senior Advisor for Vaccines 

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention 

Atlanta, GA 

MEMBERS

AULT, Kevin A, MD, FACOG, FIDSA 

Professor and Division Director 

Department of Obstetrics and Gynecology University of 

Kansas Medical Center 

Kansas City, KS 

Term: 10/26/2018 – 6/30/2022 

BAHTA, Lynn, RN, MPH, CPH 

Immunization Program Clinical Consultant 

Infectious Disease, Epidemiology, Prevention & Control Division 

Minnesota Department of Health 

Saint Paul, Minnesota 

Term: 7/1/2019 – 6/30/2023

BELL, Beth P, MD, MPH 

Clinical Professor 

Department of Global Health, School of Public Health 

University of Washington 

Seattle, WA 

Term: 7/1/2019 – 6/30/2023 
ACIP Meeting Summary May 5, 2021

30

BERNSTEIN, Henry, DO, MHCM, FAAP 

Professor of Pediatrics 

Zucker School of Medicine at Hofstra/Northwell 

Cohen Children’s Medical Center 

New Hyde Park, NY 

Term: 11/27/2017-06/30/2021 

CHEN, Wilbur H, MD, MS, FACP, FIDSA 

Professor of Medicine 

Center for Vaccine Development and Global Health 

University of Maryland School of Medicine 

Baltimore, MD 

Term: 12/23/2020 – 6/30/2024 

DALEY, Matthew F, MD 

Senior Investigator 

Institute for Health Research, Kaiser Permanente Colorado 

Associate Professor of Pediatrics 

University of Colorado School of Medicine 

Aurora, CO 

Term: 1/4/2021 – 6/30/2024 

FREY, Sharon E, MD 

Professor and Associate Director of Clinical Research 

Clinical Director, Center for Vaccine Development 

Division of Infectious Diseases, Allergy and Immunology 

Saint Louis University Medical School 

Saint Louis, MO 

Term: 11/27/2017-06/30/2021 

KOTTON, Camille Nelson, MD, FIDSA, FAST 

Clinical Director, Transplant and Immunocompromised Host Infectious Diseases 

Infectious Diseases Division, Massachusetts General Hospital 

Associate Professor of Medicine, Harvard Medical School 

Boston, MA 

Term: 12/23/2020 – 6/30/2024 

LEE, Grace M, MD, MPH 

Associate Chief Medical Officer for Practice Innovation 

Lucile Packard Children’s Hospital 

Professor of Pediatrics, Stanford University School of Medicine 

Stanford, CA 

Term: 7/1/2016 – 6/30/2021 
ACIP Meeting Summary May 5, 2021

31

LONG, Sarah S, MD 

Professor of Pediatrics 

Drexel University College of Medicine 

Section of Infectious Diseases 

St. Christopher’s Hospital for Children 

Philadelphia, Pennsylvania 

Term: 12/24/2020 – 6/30/2024 

MCNALLY, Veronica V, JD 

President and CEO Franny 

Strong Foundation 

West Bloomfield, Michigan 

Term: 10/31/2018 – 6/30/2022 

POEHLING, Katherine A, MD, MPH 

Professor of Pediatrics and Epidemiology and Prevention 

Director, Pediatric Population Health 

Department of Pediatrics 

Wake Forest School of Medicine 

Winston-Salem, NC 

Term: 7/1/2019 – 6/30/2023 

SÁNCHEZ, Pablo J, MD 

Professor of Pediatrics 

The Ohio State University – Nationwide Children’s Hospital 

Divisions of Neonatal-Perinatal Medicine and Pediatric Infectious Diseases 

Director, Clinical & Translational Research (Neonatology) 

Center for Perinatal Research 

The Research Institute at Nationwide Children's Hospital Columbus, Ohio 

Term: 7/1/2019 – 6/30/2023 

TALBOT, Helen Keipp, MD 

Associate Professor of Medicine 

Vanderbilt University 

Nashville, TN 

Term: 10/29/2018 – 6/30/2022 

EX OFFICIO MEMBERS 

Centers for Medicare and Medicaid Services (CMS)

HANCE, Mary Beth 

Senior Policy Advisor 

Division of Quality, Evaluations and Health Outcomes 

Children and Adults Health Programs Group 

Center for Medicaid, CHIP and Survey & Certification Centers 

for Medicare and Medicaid Services Baltimore, MD 
ACIP Meeting Summary May 5, 2021

32

Food and Drug Administration (FDA) 

FINK, Doran, MD, PhD 

Deputy Director, Clinical, Division of Vaccines and Related Products Applications 

Office of Vaccines Research and Review 

Center for Biologics Evaluation and Research 

Food and Drug Administration 

Silver Spring, MD 

Health Resources and Services Administration (HRSA) 

RUBIN, Mary, MD 

Chief Medical Officer 

Division of Injury Compensation Programs 

Rockville, MD 

Indian Health Service (IHS) 

WEISER, Thomas, MD, MPH 

Medical Epidemiologist 

Portland Area Indian Health Service 

Portland, OR 

Office of Infectious Disease and HIV/AIDS Policy (OIDP)

KIM, David, MD, MA 

Director, Division of Vaccines, OIDP 

Office of the Assistant Secretary for Health 

Department of Health and Human Services 

Washington, DC 

National Institutes of Health (NIH) 

BEIGEL, John, MD 

Associate Director for Clinical Research 

Division of Microbiology and Infectious Diseases 

National Institute of Allergy and Infectious Diseases (NIAID) Bethesda, MD 

LIAISON REPRESENTATIVES 

American Academy of Family Physicians (AAFP)

ROCKWELL, Pamela G, DO 

Associate Professor, Department of Family Medicine, University of 

Michigan Medical School 

Medical Director, Dominos Farms Family Medicine 

Ann Arbor, MI 

American Academy of Pediatrics (AAP) 

MALDONADO, Yvonne, MD 

Senior Associate Dean for Faculty Development and Diversity 

Professor of Pediatrics and Health Research and Policy 

Chief, Division of Pediatric Infectious Diseases 

Stanford University School of Medicine Stanford, CA 
ACIP Meeting Summary May 5, 2021

33

American Academy of Pediatrics (AAP) 

Red Book Editor

KIMBERLIN, David, MD 

Professor of Pediatrics 

Division of Pediatric Infectious Diseases 

The University of Alabama at Birmingham School of Medicine Birmingham, AL 

American Academy of Physician Assistants (AAPA) 

LÉGER, Marie-Michèle, MPH, PA-C 

Senior Director, Clinical and Health Affairs 

American Academy of Physician Assistants Alexandria, VA 

American College Health Association (ACHA) 

CHAI, Thevy S., MD 

Director of Medical Services 

Campus Health Services 

University of North Carolina at Chapel Hill Chapel Hill, 

NC 

American College Health Association (ACHA) (alternate) 

MCMULLEN, Sharon, RN, MPH, FACHA 

Assistant Vice President of Student & Campus Life for Health and Wellbeing Cornell Health 

Ithaca, NY 

American College of Nurse Midwives (ACNM) 

HAYES, Carol E., CNM, MN, MPH 

Lead Clinician 

Clinical Quality Compliance and Management 

Planned Parenthood Southeast Atlanta, GA 

American College of Nurse Midwives (ACNM) (alternate) 

MEHARRY, Pamela M., PHD, CNM 

Midwifery Educator, Human Resources for Health 

In partnership with University of Rwanda and University of Illinois, Chicago 

American College of Obstetricians and Gynecologists (ACOG) 

ECKERT, Linda O, MD, FACOG 

Professor, Department of Obstetrics & Gynecology 

Adjunct Professor, Department of Global Health 

University of Washington 

Seattle, WA

American College of Physicians (ACP) 

GOLDMAN, Jason M, MD, FACP 

Affiliate Assistant Professor of Clinical Biomedical Science, Florida Atlantic University, Boca 

Raton, Florida 

Private Practice 

Coral Springs, FL 
ACIP Meeting Summary May 5, 2021

34

American Geriatrics Society (AGS) 

SCHMADER, Kenneth, MD 

Professor of Medicine-Geriatrics Geriatrics 

Division Chief 

Duke University and Durham VA Medical Centers 

Durham, NC 

America’s Health Insurance Plans (AHIP) 

GLUCKMAN, Robert A, MD, MACP 

Chief Medical Officer, Providence Health Plans 

Beaverton, OR 

American Immunization Registry Association (AIRA) 

COYLE, Rebecca, MSEd 

Executive Director, AIRA Washington, DC 

American Medical Association (AMA)

FRYHOFER, Sandra Adamson, MD 

Adjunct Associate Professor of Medicine Emory 

University School of Medicine 

Atlanta, GA 

American Nurses Association (ANA) 

RITTLE, Charles (Chad), DNP, MPH, RN Assistant 

Professor, Nursing Faculty 

Chatham University, School of Health Sciences 

Pittsburgh, PA 

American Osteopathic Association (AOA) 

GROGG, Stanley E, DO 

Associate Dean/Professor of Pediatrics 

Oklahoma State University-Center for Health Sciences 

Tulsa, OK 

American Pharmacists Association (APhA) 

FOSTER, Stephan L, PharmD CAPT 

(Ret) USPHS 

Professor, College of Pharmacy 

University of Tennessee Health Sciences Center 

Memphis, TN 

Association of Immunization Managers (AIM) 

HOWELL, Molly, MPH 

Immunization Program Manager 

North Dakota Department of Health

Bismarck, ND 
ACIP Meeting Summary May 5, 2021

35

Association for Prevention Teaching and Research (APTR) 

McKINNEY, W Paul, MD 

Professor and Associate Dean 

University of Louisville School of Public Health and Information Sciences

Louisville, KY 

Association of State and Territorial Health Officials (ASTHO) 

SHAH, Nirav D, MD, JD 

Director

Maine Center for Disease Control and Prevention

Augusta, ME 

Biotechnology Industry Organization (BIO) 

ARTHUR, Phyllis A, MBA 

Senior Director, Vaccines, Immunotherapeutics and Diagnostics Policy 

Washington, DC 

Council of State and Territorial Epidemiologists (CSTE) 

HAHN, Christine, MD 

State Epidemiologist 

Office of Epidemiology, Food Protection and Immunization Idaho 

Department of Health and Welfare 

Boise, ID 

Council of State and Territorial Epidemiologists (CSTE) (alternate) 

LETT, Susan, MD, MPH 

Medical Director, Immunization Program 

Division of Epidemiology and Immunization 

Massachusetts Department of Public Health 

Boston, MA 

Canadian National Advisory Committee on Immunization (NACI) 

QUACH, Caroline, MD, MSc 

Pediatric Infectious Disease Specialist and Medical Microbiologist 

Medical Lead, Infection Prevention and Control Unit 

Medical Co-director – Laboratory Medicine, Optilab 

Montreal-CHUM 

Montreal, Québec, Canada 

Infectious Diseases Society of America (IDSA) 

BAKER, Carol J., MD 

Professor of Pediatrics 

Molecular Virology and Microbiology 

Baylor College of Medicine 

Houston, TX 
ACIP Meeting Summary May 5, 2021

36

International Society for Travel Medicine (ISTM) 

BARNETT, Elizabeth D, MD Professor of 

Pediatrics 

Boston University School of Medicine 

Boston, MA 

National Association of County and City Health Officials (NACCHO)

ZAHN, Matthew, MD 

Medical Director, Epidemiology 

Orange County Health Care Agency 

Santa Ana, CA 

National Association of County and City Health Officials (NACCHO) (alternate)

DUCHIN, Jeffrey, MD 

Health Officer and Chief, Communicable Disease

Epidemiology and Immunization Section 

Public Health - Seattle and King County 

Professor in Medicine 

Division of Allergy and Infectious Diseases 

University of Washington School of Medicine and School of Public Health

Seattle, WA 

National Association of Pediatric Nurse Practitioners (NAPNAP) 

STINCHFIELD, Patricia A, RN, MS, CPNP 

Director 

Infectious Disease/Immunology/Infection Control

Children's Hospitals and Clinics of Minnesota 

St. Paul, MN 

National Foundation for Infectious Diseases (NFID) 

SCHAFFNER, William, MD 

Chairman, Department of Preventive Medicine 

Vanderbilt University School of Medicine 

Nashville, TN 

National Foundation for Infectious Diseases (NFID) (alternate)

DALTON, Marla, PE, CAE 

Executive Director & CEO 

National Foundation for Infectious Diseases (NFID) 

Bethesda, MD 

National Medical Association (NMA) 

WHITLEY-WILLIAMS, Patricia, MD Professor and Chair 

University of Medicine and Dentistry of New Jersey Robert Wood 

Johnson Medical School 

New Brunswick, NJ 
ACIP Meeting Summary May 5, 2021

37

Pediatric Infectious Diseases Society (PIDS) 

O’LEARY, Sean, MD, MPH 

Associate Professor of Pediatrics 

Pediatric Infectious Diseases 

General Academic Pediatrics 

Children’s Hospital Colorado 

University of Colorado School of Medicine 

Pediatric Infectious Diseases Society (PIDS) (alternate)

SAWYER, Mark H, MD 

Professor of Clinical Pediatrics 

University of California, San Diego School of Medicine 

San Diego, CA

Pharmaceutical Research and Manufacturers of America (PhRMA) 

ROBERTSON, Corey, MD, MPH 

Senior Director, US Medical, Sanofi Pasteur 

Swiftwater, PA 

Society for Adolescent Health and Medicine (SAHM) 

MIDDLEMAN, Amy B, MD, MSEd, MPH 

Professor of Pediatrics 

Chief, Section of Adolescent Medicine 

University of Oklahoma Health Sciences Center

Oklahoma City, OK 

Society for Healthcare Epidemiology of America (SHEA)

DREES, Marci, MD, MS 

Chief Infection Prevention Officer & Hospital Epidemiologist 

ChristianaCare 

Wilmington, DE 

Associate Professor of Medicine 

Sidney Kimmel Medical College at Thomas Jefferson University Philadelphia, PA 
ACIP Meeting Summary May 5, 2021

38

ACRONYMS USED IN THE DOCUMENT

AAFP American Academy of Family Physicians 

AAP American Academy of Pediatrics

ABM Agent-Based Model 

ACHA American College Health Association 

ACIP Advisory Committee on Immunization Practices

ACOG American College of Obstetricians and Gynecologists

ACP American College of Physicians 

ADE Antibody-Dependent Enhancement 

AE Adverse Event

AHIP America’s Health Insurance Plans

AIM Association of Immunization Managers 

AIRA American Immunization Registry Association 

AMA American Medical Association

AOA American Osteopathic Association 

APhA American Pharmacists Association 

APRN Advanced Practice Registered Nurse

AS American Samoa

ASTHO Association of State and Territorial Health Officers 

BSL-4 Biosafety Level-4 

CDC Centers for Disease Control and Prevention

CLIA Clinical Laboratory Improvement Amendments 

CMS Center for Medicare and Medicaid Services

COI Conflict of Interest 

CSTE Council of State and Territorial Epidemiologists 

CYD-TDV Recombinant, Live-Attenuated, Tetravalent Chimeric Dengue Vaccine 

DFO Designated Federal Official

DSMB Data Safety Monitoring Board 

ED Emergency Department

ELISA Enzyme-Linked Immunosorbent Assay 

EtR Evidence to Recommendations

FDA Food and Drug Administration

FSM Federated States of Micronesia 

GMT Geometric Mean Titers 

GRADE Grading of Recommendation Assessment, Development and Evaluation 

HCP Healthcare Personnel / Providers

HCW Healthcare Workers 

HDCV Human Diploid Cell Vaccine 

HHS (Department of) Health and Human Services

HIV Human Immunodeficiency Virus 

HRSA Health Resources and Services Administration 

ICER Incremental Cost-Effectiveness Ratio 

IDSA Infectious Disease Society of America 

Ig Immunoglobulin

IHS Indian Health Service 

IM Intramuscular 

ISO Immunization Safety Office
ACIP Meeting Summary May 5, 2021

39

MMWR Morbidity and Mortality Weekly Report

MI Multiple Imputation 

NACCHO National Association of County and City Health Officials 

NACI National Advisory Committee on Immunization Canada

NAPNAP National Association of Pediatric Nurse Practitioners 

NCEZID National Center for Emerging and Zoonotic Infectious Diseases 

NCIRD National Center for Immunization and Respiratory Diseases 

NFID National Foundation for Infectious Diseases 

NIH National Institutes of Health

NMA National Medical Association 

NPV Negative Predictive Value 

PCECV Purified Chick Embryo Cell Vaccine 

PCP Primary Care Practitioner

PCR Polymerase Chain Reaction 

PEP Post-Exposure Prophylaxis

PHAC Public Health Agency Canada 

PhRMA® Pharmaceutical Research and Manufacturers of America®

PIDS Pediatric Infectious Disease Society 

PPE Personal Protective Equipment 

PPV Positive Predictive Value 

PrEP Pre-Exposure Prophylaxis 

PR Puerto Rico

PR Puerto Rico 

QALY Quality-Adjusted Life-Year 

RIG Rabies Immune Globulin 

RR Relative Risk

RVA Rabies Vaccine Adsorbed 

RVV Rabies Virus Variants 

SAE Serious Adverse Event 

SAGE Strategic Advisory Group of Experts on Immunization (WHO)

SAHM Society for Adolescent Health and Medicine 

SHEA Society for Healthcare Epidemiology of America 

US United States

USG US Government 

USVI United States Virgin Islands 

VAERS Vaccine Adverse Event Reporting System

VFC Vaccines For Children

VRBPAC Vaccine and Related Blood Products Advisory Committee 

WG Work Group

WHO World Health Organization