Pandemics past, present, and future: progress and persistent risks

Full text

The Journal of Clinical Investigation JCI 100TH ANNIVERSARY VIEWPOINT
1
Pandemics past, present, and future:
progress and persistent risks
Arturo Casadevall
Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, Maryland, USA.
When the JCI began publishing in ,
the world was recovering from the end of
the First World War and the lingering after-
math of the  influenza pandemic. The
th anniversary of the JCI occurs nearly
ive years since the initial appearance of
COVID, caused by SARSCoV. I was
a JCI deputy editor during the early years
of the COVID pandemic, when I wit-
nessed irsthand how the pandemic affect-
ed journal operations and how the Journal
published a series of important articles
that deined the disease and the immune
response and helped catalyze early medical
responses . The JCI has now published
through ive pandemics, three caused by
influenza virus in , , and ,
one caused by the retrovirus HIV that
began in , and another caused by the
coronavirus SARSCoV in . In this
essay, I will reflect on what we have learned
from these ive pandemics and try to iden-
tify themes that could help with future
global infectious disease outbreaks.
Pandemics begin suddenly and
never really end
All pandemics surprise humanity. Whereas
the beginning of a pandemic can usually be
established, it is not clear when pandem-
ics end, or whether they really end. The
black death of the Middle Ages caused by
Yersinia pes tis began in , abated in ,
recurred several times, and may have left
the bacterium endemic in affected areas
. For the ive pandemics that occurred
since the launching of the JCI, none has
really ended. At the time of this writing,
virus descendants from the influenza 
strain, HIV, and SARSCoV pandemics
are still with us. In fact, all seasonal and
pandemic influenza virus strains for the
past century have some ancestry to the 
virus, which has prompted Taubenberger
and Morens to state that “the impact of
the pandemic virus — now known to be an
HN influenza A virus — was not, howev-
er, limited to . The  influenza
A virus became a ‘founder virus,’ initiating
a ‘pandemic era’ by evolving into progeny
pandemic viruses through a number of
separate genetic reassortment events” .
Each pandemic has in common the intro-
duction into the human population of a
new communicable agent for which there
was initially little to no immunity that then
spread widely and became established,
thus changing the future dynamics of the
host-microbe interaction.
Pandemic agents are
unpredictable
In , I learned in medical school that
retroviruses were good systems to study
how viruses caused cancer but were not
agents of human disease and that corona-
viruses were minor pathogens that caused
annoying upper respiratory infections. I
relate this anecdote because two of the
subsequent pandemics — those involving
HIV and SARSCoV — were caused by
a retrovirus and coronavirus, respective-
ly, highlighting how medical knowledge
evolves. In , the human T cell leu-
kemia virus was discovered and subse-
quently shown to cause T cell lymphoma,
establishing that retroviruses were patho-
genic for humans and foreshadowing the
HIV pandemic, which would be caused
by another retrovirus . Similarly, the
medical world was surprised in  by
the outbreak of a respiratory coronavirus
known as SARSCoV, which caused pneu-
monia with high mortality. Fortunately,
SARSCoV did not develop into a pandem-
ic. In , another coronavirus MERS-
CoV was described in the Middle East
that caused severe respiratory disease with
high mortality but was less contagious,
and the outbreak has remained region-
al. The near brushes with SARSCoV and
MERSCoV were not suficient to illustrate
the pandemic danger posed by coronavi-
ruses, and humanity was surprised by the
COVID pandemic. Prior to COVID,
much of the concern in medical circles
was the possibility of a new influenza pan-
demic caused by a highly pathogenic avian
influenza virus, such as HN, illustrating
a weakness in the preparedness mindset
that prioritized agents known to cause pri-
or pandemics. One common denominator
for the major pandemics since  is a
likely zoonotic origin for the viruses caus-
ing the  influenza , HIV , 
HN , and COVID  pandemics
and a probable zoonotic genetic input for
the  HN and  HN influ-
enza viruses . Hence, while pandemics
are unpredictable, contact with the animal
world can be anticipated to be a continuing
source of new pandemic agents.
Response to pandemics shows
the progress of science
The ive pandemics in the time of the JCI,
together with the  influenza pandemic,
show how the progress of science over the
past century has mitigated the catastroph-
ic potential of infectious disease outbreaks
Table . For the  influenza pandem-
ic, the etiologic agent was unknown, as the
isolation of the causative agent would have
to wait until , when the influenza virus
was irst isolated from humans. For the
 influenza pandemic, there were no
vaccines, antiviral drugs, or supplemental
oxygen, and the only speciic therapy was
convalescent serum, which retrospective
analysis suggested reduced mortality by
approximately  . The irst pan-
demic during the JCI’s existence, and the
second for the th century, was the 
to  influenza pandemic, which began
Conflict of interest: AC is a member of the scientific advisory board of Sab Therapeutics.
Copyright: © 2024, Casadevall et al. This is an open access article published under the terms of the Creative Com-
mons Attribution 4.0 International License.
Reference information: J Clin Invest. 2024;134(7):e179519. https://doi.org/10.1172/JCI179519.

The Journal of Clinical Investigation
JCI 100TH ANNIVERSARY VIEWPOINT
2J Clin Invest. 2024;134(7):e179519 https://doi.org/10.1172/JCI179519
off during that pandemic . For the pan-
demics of  and , vaccines were
available, but for HIV, no successful vac-
cine has yet been developed despite con-
siderable research efforts.
New infectious disease
assaults from nature are
inevitable
The irst  years of the st century saw at
least eight major viral outbreaks, includ-
ing West Nile, SARSCoV, HN, MERS-
CoV, Zika, Ebola, SARSCoV, and mpox,
three of which were new viruses and two
of which resulted in pandemics. Given this
record, we can expect continuing infec-
tious disease assaults from nature in the
years ahead. Whereas viruses loom large
among potential threats, the black death,
which is arguably the greatest calamity in
recorded times, was caused by the bac-
terium Yersinia pestis. Humanity tends to
worry about known threats and, conse-
quently, is frequently surprised. In mili-
tary history, there is the well-known say-
ing that generals always prepare to ight
the last war, but medicine should not fall
into this trap, given that two of the last ive
pandemics were caused by new agents. In
this regard, I note that fungal diseases are
not high in threat assessments because
there is no prior experience with pandem-
ics caused by fungi. However, with regard
advances in molecular biology allowed
the identiication of the virus three years
after the irst cases were identiied, and
antiviral therapy was available later in the
decade, such that the resulting disease,
acquired immunodeiciency syndrome
AIDS, went from being uniformly lethal
to a manageable disease, if treated prop-
erly. In comparison with the four previ-
ous pandemics, the COVID pandemic
stands alone in the rapid development of
antibody therapies, antiviral drugs, and
effective vaccines within a year of the
beginning of the outbreak. This rapidity
illustrates the progress of science, which
included the development of mRNA vac-
cines that proved remarkably effective
in preventing death, although the rapid
evolution of SARSCoV meant frequent
breakthrough infections among the vacci-
nated. Administration of mRNA vaccines
during pregnancy produced a robust anti-
body response that transferred immunity
to the fetus within  days of vaccination
. This result encouraged vaccination
during pregnancy as a means of protecting
newborns against SARSCoV. Although
the application of mRNA technology to
vaccine development for COVID was
novel, this technology relied on decades
of immunological, virological, and bio-
chemical research and showed how earlier
societal investments in basic research paid
in Asia with the emergence of the HN
influenza strain. Three articles published
in the JCI in  illustrate the tremendous
progress in medical knowledge that had
occurred in the four decades since the 
influenza pandemic, including the discov-
ery of the virus and methods for its culti-
vation, the development of vaccines, and
the emergence of clinical immunology as a
ield. The irst article reported less severe
disease among the cohort that had been
previously vaccinated, anticipating what
is now accepted that vaccination reduces
disease severity and death even when it
does not prevent disease . The second
article reported the occurrence of bacteri-
al pneumonia as a major late complication
of influenza pneumonia and noted that
many cases were caused by Staphylococcus
aureus , but by  antibiotic thera-
py was available, reducing mortality. The
third article detailed the isolation of the
influenza virus from throat washing and
lung tissue of patients who died, compared
various methods of virus culturing, and
included an electron micrograph of virions
from culture, demonstrating tremendous
progress in virological techniques .
In contrast to the irst three pandem-
ics of the th century, each caused by
the influenza virus, the HIV pandemic
involved a retrovirus not previously known
to the medical ield. By the early s,
Table 1. Medical progress since the 1918 influenza pandemic
Pandemic
Year 1918 1957 1968 1981 2009 2019
Virus H1N1 H2N2 H3N2 HIV H1N1 SARS-CoV-2
Time to virus discovery 14 years Weeks Weeks 3 years Weeks Weeks
Diagnosis Clinical Viral culture serology Viral culture serology Serology NAATAViral culture NAAT NAAT rapid testsB
Therapy
Sera/plasmaCYes No No No ExperimentalDYes
Antiviral No No Yes Yes Yes Yes
mAb No No No Experimental Experimental Yes
Vaccine No Yes Yes Experimental Yes Yes
ANAAT, nucleic acid amplification test. For HIV, serology was developed first, followed by NAAT years later. BRapid diagnostic tests for COVID-19 were a
major innovation during the pandemic that allowed infected individuals to determine within minutes if they were positive for SARS-CoV-2. These tests
were marketed for home testing, giving individuals the ability to determine their potential infectiousness and were a major tool for preventing the spread
of infection. CBy the 1950s, the use of convalescent sera had been abandoned because of the association with serum hepatitis, which was eventually
discovered to be caused by hepatitis viruses. Hence, neither convalescent serum nor plasma was used in the 1957 or 1968 pandemics. For HIV, disease
occurred despite serum antibodies, and its use was not considered. However, for the 2009 and 2019 pandemics, advances in blood transfusion medicine
allowed screening for known agents of blood-borne diseases such as HIV and hepatitis viruses, and convalescent plasma was again an option that was
widely used in the first year of the COVID-19 pandemic. DExperimental means that the vaccine or therapy was in clinical research development during the
pandemic. For HIV, a mAb has been developed for use in individuals with drug-resistant viral infection, and several vaccines are in development, but none
has yet been successfully deployed despite great efforts.

The Journal of Clinical Investigation JCI 100TH ANNIVERSARY VIEWPOINT
3
J Clin Invest. 2024;134(7):e179519 https://doi.org/10.1172/JCI179519
and communication to better understand
human behavior and social structures in
the response to emergencies. g Climate
change due to anthropogenic warming
heightens the risk of new pandemics by
changing such variables as the introduc-
tion of new infectious diseases and a less-
ening of societal resilience in responding
to heat-related stresses on agriculture,
economics, and infrastructure.
Each pandemic brought untold suffer-
ing to those affected, but each pandemic
was also accompanied by great learning
and much scientiic progress. We are just
beginning to process the lessons from the
COVID pandemic, and I am optimistic
that they will also catalyze great progress.
Each pandemic left us in better shape to
ight future pandemics because humanity
learned and made investments in science
and public health that increased prepared-
ness against the unpredictable. There are
more pandemics ahead, and such invest-
ments must continue to mitigate the great
danger they pose to humanity.
Address correspondence to: Arturo Casa-
devall, Department of Molecular Micro-
biology and Immunology, Johns Hopkins
School of Public Health,  N. Wolfe
Street, Room E, Baltimore, Maryland
, USA. Phone: ..; Email:
acasadevall@jhu.edu.
. Casadevall A, et al. The Journal of Clinical Inves-
tigation in the time of COVID. J Clin Invest.
;:e.
. Parker CE, et al. th century Yersinia
pestis genomes support emergence of pes-
tis secunda within Europe. PLoS Pathog.
;:e.
. Taubenberger JK, Morens DM. The  influ-
enza pandemic and its legacy. Cold Spring Harb
Perspect Med . ;:a.
. Cofin JM. The discovery of HTLV, the irst
pathogenic human retrovirus. Proc Natl Acad Sci
U S A. ;: .
. Sharp PM, Hahn BH. Origins of HIV and the
AIDS pandemic. Cold Spring Harb Perspect Med.
;:a.
. Taubenberger JK, et al. Reconstruction of the
 influenza virus: unexpected rewards from
the past. mBio. ; :e.
. Boni MF, et al. Evolutionary origins of the
SARSCoV sarbecovirus lineage responsible
for the COVID pandemic. Nat Microbiol.
;:.
. Taubenberger JK, Morens DM. Influenza: the
once and future pandemic. Public Health Rep.
;suppl :.
. Luke TC, et al. Meta-analysis: convalescent
blood products for Spanish influenza pneumonia:
Temperature affects every chemical reac-
tion necessary for life, and rapid global
warming is an existential threat for many
species, including our own. Much has been
written about the effects of climate change
on infectious diseases, and a consensus is
emerging that it can amplify the progres-
sion of infectious disease outbreaks to
pandemics . The confluence of climate
change with a rising human population
and an increasingly degraded environ-
ment create conditions propitious for new
pandemics. In this regard, global warming
will force changes to human and animal
behavior that can signiicantly increase
the likelihood of zoonotic spillovers and
trigger new pandemics . In addition,
global warming will force the adaptation
of many microbes with human pathogen-
ic potential to survive at higher tempera-
tures, such that these microbes can then
thrive at human temperatures and defeat
our thermal defenses. The emergence
of Candida auris, a fungal pathogen that
has now spread globally after simultane-
ous, independent emergences, has been
proposed to be a result of climate change
 and may be a harbinger of new future
infectious disease threats, some of which
could have pandemic potential.
Seven evolving themes from
a century of pandemics
Looking back through the ive pandemics
in the century of the JCI’s existence allows
one to discern seven themes that are like-
ly to recur as humanity faces new dangers
from infectious diseases in the years ahead.
a Pandemics are unpredictable. b Most
pandemics never end, as the agent evolves
to ind a continued niche in human popula-
tions. c Continued investment in science
and preparedness is the best insurance pol-
icy against future pandemics. d Pandem-
ics with new infectious disease agents pose
the greatest danger, since countermea-
sures such as vaccines and new drugs will
not be immediately available to contain
the outbreak. e Human nature is often
an ally of infectious disease outbreaks and
spread, with human actions potentially
interfering with public health efforts to
mitigate suffering and death. f Progress
against future pandemics requires not only
scientiic advances but also improvements
in how physicians evaluate evidence as
well as advances in the social sciences
to fungi, nature provides clear warnings
such as, for example, the ongoing global
pandemic of chytridiomycosis that has led
to the extinction of multiple frog species
and the fungi that are currently decimat-
ing numerous ecosystems that include
bats in North America and salamanders
in Europe . Although it is not possible
to predict the cause of the next pandem-
ic, preparedness must include a holistic
assessment of possible threats, includ-
ing agents that have not been historically
implicated in human disease.
Human nature as an ally
to pandemic microbes
Despite the tremendous medical advanc-
es that spanned the century between the
 influenza and COVID pandem-
ics, human nature was constant and often
acted as an ally to the viruses. In ,
despite no knowledge about the causative
organism, public health authorities cor-
rectly surmised that they were dealing
with a respiratory pathogen and passed
mask mandates that were resisted by
many citizens. A century later, COVID
was known to be a respiratory pathogen,
and masks were again recommended by
public health authorities and resisted by
many citizens. Both the  influenza and
COVID pandemics saw citizen resis-
tance to public health mandates, although
in the case of COVID, some of the resis-
tance was political . Even the develop-
ment of safe and effective vaccines found
resistance, and in the United States alone,
vaccine hesitancy cost over , lives
. However, the problem of faulty inter-
pretation of medical evidence was not
limited to the general public, given the
fact that the medical profession misinter-
preted the clinical evidence available for
hydroxychloroquine, corticosteroids, and
convalescent plasma, leading to actions
that were associated with higher mortal-
ity . Hence, future progress in pan-
demic responses must address the social
and behavioral issues that can conspire to
interfere with effective measures, and that
includes improved training for physicians
in the evaluation of evidence.
Climate change and pandemics
The world is currently experiencing
unprecedented rapid global warming
because of anthropogenic gas emissions.

The Journal of Clinical Investigation
JCI 100TH ANNIVERSARY VIEWPOINT
4J Clin Invest. 2024;134(7):e179519 https://doi.org/10.1172/JCI179519
. Jia KM, et al. Estimated preventable
COVID-associated deaths due to non-
vaccination in the United States. Eur J Epidemiol.
;: .
. Casadevall A, Pirofski LA. Misinterpretation of
clinical research indings and COVID mortal-
ity. Ann Intern Med. ;:.
. de Oliveira T, Tegally H. Will climate change
amplify epidemics and give rise to pandemics?
Science. ;:eadk.
. Carlson CJ, et al. Climate change increases
cross-species viral transmission risk. Nature.
;:.
. Casadevall A, et al. On the emergence of Can-
dida auris: climate change, azoles, swamps, and
birds. mBio. ;:e.
quantitative comparison of isolation methods.
J Clin Invest. ; part :.
. Beharier O, et al. Eficient maternal to neonatal
transfer of antibodies against SARSCoV and
BNTb mRNA COVID vaccine. J Clin
Invest. ;:e.
. Casadevall A. The mRNA vaccine revolution
is the dividend from decades of basic science
research. J Clin Invest. ;:e .
. Fisher MC, et al. Threats posed by the fungal
kingdom to humans, wildlife, and agriculture.
mBio. ;:e.
. Navarro JA, Markel H. Politics, pushback, and
pandemics: challenges to public health orders in
the  influenza pandemic. Am J Public Health.
;:.
a future HN treatment? Ann Intern Med.
;:.
. Blumenfeld HL, et al. Studies on influenza in the
pandemic of . I. An epidemiologic,
clinical and serologic investigation of an intra-
hospital epidemic, with a note on vaccination
eficacy. J Clin Invest. ; part : .
. Louria DB, et al. Studies on influenza in the
pandemic of . II. Pulmonary
complications of influenza. J Clin Invest.
; part : .
. Kilbourne ED. Studies on influenza in the pan-
demic of . III. Isolation of influenza
A Asian strain viruses from influenza patients
with pulmonary complications; details of virus
isolation and characterization of isolates, with