Elsevier

Vaccine

Volume 38, Issue 7, 11 February 2020, Pages 1589-1592
Vaccine

Short communication
Evidence of vaccinia dissemination despite lack of major reaction following smallpox vaccination

https://doi.org/10.1016/j.vaccine.2019.12.046Get rights and content

Abstract

Following vaccinia vaccination, vesicle formation at the site occurs in 95% of primary vaccinees and is thought to indicate virus replication and vaccine efficacy. Little is known about virus replication and immune response in those who do not develop a vesicle. We used PCR to detect vaccinia in various sites following receipt of the smallpox vaccine in those with and without vesicle formation. Among 80 participants, 74 developed and 6 failed to develop a vesicle. Vaccinia DNA was detected in the blood, in the oropharynx, on the dressing, and on the hands of 5%, 11%, 4%, and 0% of those with vesicle formation and of 33%, 17%, 0%, and 17% of those without vesicle formation, respectively (p > 0.05 for each site). The detection of systemic vaccinia DNA in vaccinees without vesicle formation challenges the current understanding that lack of vesicle formation indicates lack of virus replication, the prerequisite to immune response.

Introduction

Routine administration of the smallpox vaccine in the US ended in 1972 due to concerns the risks outweighed the benefits. Although the last naturally occurring case of smallpox was in 1977, threats of bioterrorism prompted the Department of Defense (DoD) and the Department of Health and Human Services (DHHS) to initiate a new smallpox vaccination program in the US in 2002. Although the production techniques and strains used in smallpox vaccines vary globally, all contain live vaccinia virus. In addition to being used as a vaccine to protect against orthopox infections, vaccinia is being widely studied as a component of vector-based vaccines against numerous infections including hepatitis C and HIV.

Smallpox vaccination is unique in that it requires a very small amount of reconstituted vaccine be withdrawn from a vial with a bifurcated needle, placed on the skin and administered into the superficial layers of the skin through multiple punctures. Vesicle formation at the site of administration, termed a major reaction, has been considered satisfactory evidence of a successful vaccination and should occur by the 5th day [1], [2]. It has been thought to indicate virus replication and has been correlated with the production of specific antibodies and induction of cytotoxic T lymphocyte and interferon-gamma T cell responses [3], [4]. The package insert for the smallpox vaccine currently licensed in the US (ACAM2000, Emergent BioSolutions, Inc., Gaithersburg, MD), states that lack of vesicle formation indicates vaccination failure due to either impotent vaccine or inadequate vaccination technique [5].

About 95% of primary vaccinees develop a vesicle: vaccinia DNA can be detected at the vaccination site of almost all and in the oropharynx and blood of some [6], [7], [8]. This suggests both local and disseminated virus replication. Current guidance is to consider those who do not develop a vesicle nonimmune and to readminister the vaccine up to twice more. Here we describe the use of real-time PCR to determine the presence of vaccinia virus in the blood, in the oropharynx, on the external surface of the dressing covering the vaccination site, and on the hands, following receipt of the smallpox vaccine in those with and without vesicle formation.

Section snippets

Material and methods

This prospective trial was approved by the David Grant USAF Medical Center, Travis AFB, CA, Institutional Review Board, and DHHS guidelines for human experimentation were followed. Active duty military members receiving the smallpox vaccine in accordance with DoD and CDC guidelines were eligible to participate in the study. All subjects provided written informed consent and were enrolled between April 2003 and April 2004.

The vaccine used in the study was the New York City Board of Health strain

Results

Of 97 individuals enrolled, 14 were lost to follow-up. The mean age of participants was 30 years (range 18 to 56). Eighty of 83 patients returned for the D7 visit. Among these 80, 74 developed and 6 failed to develop a vesicle at the vaccination site. Baseline demographics and vaccination history were similar among those with and without vesicle formation (Table 1).

Twelve of 74 participants (16%) with vesicle formation and 2 of 6 (33%) without vesicle formation had at least one positive sample

Discussion

Although this study is limited by the small number of participants and lack of a control group or serological testing, the detection of vaccinia DNA in the oropharynx and blood of vaccinees without a major reaction suggests systemic dissemination and replication of virus. This finding challenges the current understanding that lack of vesicle formation indicates lack of viral replication, the key prerequisite to development of humoral and cell-mediated immunity (CMI). Between December 2002 and

Disclaimers

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the official policy of the Department of Defense or other Departments of the US Government.

The voluntary, fully informed consent of the subjects described in this research was obtained as required by 32 CFR 219 and AFI 40-402, Protection of Human Subjects in Biomedical and Behavioral Research.

The work reported herein was performed under United States Air

CRediT authorship contribution statement

Wilfred P. Delacruz: Methodology, Investigation, Writing - original draft, Funding acquisition. Michael R. Savona: Investigation, Data curation, Supervision, Writing - review & editing. Jennifer A. Thornton: Formal analysis, Writing - review & editing. Patrick J. Danaher: Conceptualization, Methodology, Supervision, Writing - review & editing, Funding acquisition.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. This study was funded by the United States Air Force Surgeon General.

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