The NEW ENGLA ND JOURNAL of MEDICINE

Perspective 

Monoclonal Antibodies for Emerging Infectious Diseases —

Borrowing from History
Hilary D. Marston, M.D., M.P.H., Catharine I. Paules, M.D., and Anthony S. Fauci, M.D.​​

A 
Monoclonal Antibodies for Emerging Infectious Diseases

lthough antibodies play pivotal roles in the for specific activity against a pre-
immune response to infection, they have determined target (see illustration);
moreover, there is the added ben-
seen limited use as therapeutic agents for in- efit of a high degree of consis-
fectious diseases. Yet there is a long history of plasma- tency among manufactured lots.1
Using mAbs in place of polyclonal
derived treatments for several risk infants). Recent conceptual serums has improved the safety
pathogens. Emil Adolf von Behring, and technological advances in mAb profile of immunotherapy, reduc-
for example, won the Nobel Prize development could have an enor- ing such concerns as the risk of
in Physiology or Medicine in 1901 mous impact on the field of infec- serum sickness and anaphylaxis
for the application of animal- tious diseases, particularly in the sometimes seen with animal-
derived serum therapies, principal- context of emerging infectious derived polyclonal preparations.1
ly against diphtheria.1 Since then, disease (EID) outbreaks, in which In addition, effective antibod-
plasma-based therapy has been at- the process of vaccine development ies have become easier to identify,
tempted for infectious disease out- for new pathogens may be diffi- select, optimize, and manufacture.
breaks ranging from the 1918 cult and prolonged. The rapid de- When mAbs were originally de-
influenza pandemic to Ebola out- velopment and strategic deploy- scribed in the 1970s, they were
breaks from 1976 onward. Despite ment of effective, highly specific derived from the vaccination of
this history and the rapidly accel- preventive and therapeutic inter- mice with antigens of interest and
erating development of monoclo- ventions have the potential to al- the harvesting of B cells from
nal antibodies (mAbs) for non- ter the course of an epidemic. mouse spleens.1 This technique
communicable diseases such as Research advances could facili- continues to have value today, but
cancer and autoimmune condi- tate a strategic shift toward the there are also more direct and im-
tions, only a handful of antibody use of mAbs for EIDs. For exam- proved approaches whereby rele-
therapies have been licensed for ple, unlike traditional serum vant antibodies can be identified
infectious diseases (e.g., palivi- therapy, which uses polyclonal directly from exposed persons. For
zumab for prophylaxis against antibodies, therapy using mAbs example, investigators are now
respiratory syncytial virus in at- targets a single epitope, allowing able to use flow cytometry to sort

n engl j med  nejm.org 1

The New England Journal of Medicine
Downloaded from nejm.org on March 7, 2018. For personal use only. No other uses without permission.
Copyright © 2018 Massachusetts Medical Society. All rights reserved.
PERS PE C T IV E
memory B cells on the basis of
their antigen-binding character-
istics. The variable regions of the
antibody heavy and light chains
can be cloned and monoclonal
antibodies expressed.1 From these
initial procedures, candidates for
mAb development can be further
selected on the basis of in vitro
neutralization (and other effector-
function) assays that evaluate ac-
tivity.1 With these and other tech-
niques, the time required to isolate
and characterize antibodies has
been reduced from years to weeks.
Candidate mAbs, once devel-
oped, can be optimized with a
variety of strategies, including ex-
tension of half-life through modi-
fications to the Fc portion of the
antibody molecule, an attribute
that is potentially critical for pro-
phylaxis.1 In certain settings, in-
teractions with the Fc receptor
are postulated to play a role in
pathogenesis — for example, in
antibody-dependent enhancement
of flaviviruses. Modifications to
the Fc receptor can prevent these
interactions while maintaining
neutralizing functions, potential-
ly improving safety profiles.2 Fi-
nally, manufacturing techniques
are improving, through use of
qualified, stabilized cell lines, as
well as new plant and animal
systems.
With these advances, mAbs
have the potential to increase our
effectiveness in responding to EIDs,
particularly in cases in which their
use may substantially improve pa-
tient or population-level outcomes.
However, given the current costs
of production and relative com-
plexity of administration (e.g., the
need for parenteral administra-
tion), targeted use of mAbs will
be necessary. There are three par-
ticularly compelling indications
2 n engl j med  nejm.org
The New England Journal of Medicine
Downloaded from nejm.org on March 7, 2018. For personal use only. No other uses without permission.
Copyright © 2018 Massachusetts Medical Society. All rights reserved.
Monoclonal Antibodies for Emerging Infectious Diseases
for their use: treatment of infect-
ed individuals, targeted prophy-
laxis to protect high-risk individ-
uals, and targeted prophylaxis to
interrupt transmission in aver-
age-risk populations.
The 2014–2016 Zaire ebolavirus
outbreak in West Africa demon-
strated mAbs’ promise for treat-
ment. ZMapp, a “cocktail” of three
mouse–human chimeric antibod-
ies, had demonstrated efficacy in
nonhuman primates; however, only
minimal quantities were available,
and it had not been evaluated in
humans. In February 2015, a ran-
domized, controlled trial was ini-
tiated in infected patients; how-
ever, as the incidence of Ebola
infection dropped, trial enrollment
decreased and the study failed to
reach statistical significance. Still,
the limited data set showed some
promise of a mortality benefit.3
Since then, investigators have iso-
lated multiple Ebola antibodies
that could serve as essential tools
for Ebola treatment in future out-
breaks. Some of these antibody
candidates may offer protection
with a single mAb (as opposed to
a cocktail), potentially simplify-
ing manufacturing processes and
reducing costs, and others could
provide cross-species protection
(which is important given the
threat presented by Sudan and
other Ebola virus species).4
MAbs may also play an impor-
tant role in prophylaxis for per-
sons at high risk for infection (or
adverse sequelae), such as preg-
nant women in areas where Zika
virus is circulating. Ideally, women
would be protected from infec-
tion before pregnancy with a vac-
cine. Failing that, mAbs may have
a role as passive immunization for
pregnant women, offering protec-
tion for the fetus without the
weeks’ delay required to induce an
immune response through vacci-
nation. Administration of a potent
neutralizing antibody targeting the
Zika virus envelope protein pro-
tected mice from congenital Zika
syndrome before Zika virus chal-
lenge in the mother.2 This research
required both the characterization
of mouse pregnancy models and
the isolation and production of
effective antibodies, and yet re-
sults were obtained within months
after the recognition of the Zika–
microcephaly link in humans.
Researchers hope to advance this
mAb candidate into clinical trials,
including studies in pregnant
women. Similar individual-level
prophylaxis could be envisioned
for other diseases — for exam-
ple, for health care workers and
other high-risk populations fac-
ing outbreaks of hemorrhagic fe-
ver viruses.
Furthermore, mAbs may pro-
vide population-level prophylaxis,
particularly if used to interrupt
chains of transmission. For exam-
ple, although vaccination is the
mainstay of seasonal influenza
prevention and epidemic control,
it has historically had little effect
on the course of evolving pandem-
ics because of the time it takes to
develop and deploy a vaccine
against a novel pandemic strain.
MAbs that target conserved re-
gions of the influenza virus could
bridge the time between onset of
an influenza pandemic and avail-
ability of a vaccine. Several broad-
ly neutralizing mAbs targeting the
highly conserved stem portion of
the hemagglutinin protein of in-
fluenza A have had promising re-
sults in preclinical studies against
a range of influenza subtypes
and were well tolerated in early-
stage clinical trials.5 These agents
PE R S PE C T IV E Monoclonal Antibodies for Emerging Infectious Diseases

A B C

Antigen
introduction

Infection Infection or
vaccination

Convalescence: virus cleared, Extraction of B cells Extraction of B cells from peripheral

antibody response generated from spleen blood or lymphoid tissue

Selection of B cells Selection of B cells

expressing antibodies expressing antibodies
of interest of interest

Polyclonal response Mouse monoclonal antibodies Human monoclonal antibodies

D Polyclonal Antibodies Used in Traditional Serum Therapy E Monoclonal Antibodies Targeting a Specific Epitope

Epitopes Target epitope

Surface
Surface protein
protein

VIRUS VIRUS

Monoclonal Antibody Therapy.

Panel A shows early techniques to collect polyclonal serum from individuals recovering from disease after infectious virus is cleared and anti-
body response has been generated. Panel B shows monoclonal antibody isolation from mice, using antigen introduction into mice, collection
of B cells from mouse spleens, and production of fully mouse, antigen-specific monoclonal antibodies. Panel C shows a technique for isolation
of monoclonal antibodies from humans, using antigen introduction (through natural infection or immunization), collection of immune cells
from peripheral blood or lymphoid tissue, selection of B cells expressing antibodies of interest (e.g., using flow cytometry), and production of
fully human, antigen-specific monoclonal antibodies. Panel D shows polyclonal antibodies binding diverse regions or epitopes on the virion,
whereas Panel E shows monoclonal antibodies representing a single antibody that targets a single epitope.

n engl j med nejm.org 3

The New England Journal of Medicine
Downloaded from nejm.org on March 7, 2018. For personal use only. No other uses without permission.
Copyright © 2018 Massachusetts Medical Society. All rights reserved.
PERS PE C T IV E
have therapeutic potential and
may also interrupt transmission if
administered to uninfected per-
sons who are in proximity to in-
dex cases. Transmission studies in
ferrets demonstrated that admin-
istration of one such antibody,
MEDI8852, to uninfected ferrets
can protect them from airborne
transmission of the H1N1pdm09
virus.5
Although mAbs have potential
for use in responding to EIDs,
pragmatic concerns must be ad-
dressed — notably cost. Targeted
development and deployment of
antibodies with high potency (re-
quiring less material per dose)
will help reduce the cost, as will
improvements in manufacturing.
Administration of mAbs, partic-
ularly those requiring cold stor-
age and intravenous infusion, may
also be challenging in some out-
break settings. In the future, the
EID field may turn increasingly to
high-affinity antibodies, allowing
4 n engl j med  nejm.org
The New England Journal of Medicine
Downloaded from nejm.org on March 7, 2018. For personal use only. No other uses without permission.
Copyright © 2018 Massachusetts Medical Society. All rights reserved.
Monoclonal Antibodies for Emerging Infectious Diseases
subcutaneous dosing, or novel de-
livery platforms such as nucleic
acid and vectored constructs, min-
imizing the need for intravenous
administration. Finally, EID patho-
gens probably vary in their vul-
nerability to mAbs, and particu-
larly to neutralizing antibodies.
Yet the knowledge gained in ad-
vancing the field of mAbs for
EIDs will enable the development
of other countermeasures, includ-
ing vaccines, and increasingly spe-
cific diagnostics.
Despite the challenges, mAbs
are positioned to play a larger role
in future public health responses
involving the diagnosis, prevention,
and treatment of EIDs, and the
lessons learned will most likely
apply to infectious diseases in
general. If we are to fully realize
mAbs’ promise in EIDs, leaders
in preparedness and response will
have to assign them a high prior-
ity in research and development
agendas.
Disclosure forms provided by the au-
thors are available at NEJM.org.
From the Office of the Director of the Na-
tional Institute of Allergy and Infectious
Diseases, National Institutes of Health,
Bethesda, MD.
This article was published on March 7,
2018, at NEJM.org.
1. Walker LM, Burton DR. Passive immu-
notherapy of viral infections: ‘super-anti-
bodies’ enter the fray. Nat Rev Immunol
2018 January 30 (Epub ahead of print).
2. Sapparapu G, Fernandez E, Kose N, et
al. Neutralizing human antibodies prevent
Zika virus replication and fetal disease in
mice. Nature 2016;​540:​443-7.
3. The PREVAIL II Writing Group. A ran-
domized, controlled trial of ZMapp for Ebo-
la virus infection. N Engl J Med 2016;​375:​
1448-56.
4. Mire CE, Geisbert TW. Neutralizing the
threat: pan-ebolavirus antibodies close the
loop. Trends Mol Med 2017;​23:​669-71.
5. Paules CI, Lakdawala S, McAuliffe JM, et
al. The hemagglutinin A stem antibody
MEDI8852 prevents and controls disease
and limits transmission of pandemic influ-
enza viruses. J Infect Dis 2017;​216:​356-65.
DOI: 10.1056/NEJMp1802256
Copyright © 2018 Massachusetts Medical Society.
Monoclonal Antibodies for Emerging Infectious Diseases