Embedded Files
September 2014 "Patrick Iversen of OSU and the biotech company Sarepta talks about the decade he's spent working to develop AVI-7357, a drug that could be used to treat patients infected with the Ebola virus."https://www.newspapers.com/image/631404857/?terms=%22Patrick%20Iversen%22&match=12016-11-16-albany-democrat-herald-pg-a5-clip-ebola-iversen-profile.jpg
Wikipedia 🌐 NONE
Wikipedia 🌐 NONE
Married to "Laurie Iversen" ( https://library.uoregon.edu/sites/default/files/data/news/librarypubspdf/UOLib%20BK%20FIN%20summer%202008.pdf )
ASSOCIATIONS
ASSOCIATIONS
Dr. Randall Lawrence Kincaid (born 1951) (while at the T.M.T.I ... "Randall Kincaid, a biologist and entrepreneur who that week had become the scientific director of T.M.T.I., described Iversen’s work: “He distilled the background of influenza, the intricacies of the virus itself, and the types and strategies that would likely work or not work. I thought, Man, this is a guy who either has thought about this for a long time or is incredibly smart and in a few days came up with this. Either way, it is great.” ) - 2011(Jan) New Yorker article : [HP008I][GDrive]
Sina A Bavari (born 1959) ( Significant research effort collaboration between Iversen and Bavari in 2000s and 2010s. Several articles written in 2020 and 20201 regarding COVID19 vaccines, with only Bavari and Iversen as the authors. )
COMPANIES
COMPANIES
Sarepta Therapeutics (AVI BioPharma) ( long career ...)
2021 (Oct 25) - LinkedIn.com : "Profile for Patrick Iversen - Member at Knight Cancer Research Institute, OHSU"
2021 (Oct 25) - LinkedIn.com : "Profile for Patrick Iversen - Member at Knight Cancer Research Institute, OHSU"
https://www.linkedin.com/in/patrick-iversen-649471b/
2021-10-linkedin-com-patrick-iversen-649471b.pdf
https://drive.google.com/file/d/1whdFdD4tIoYWEzmAFYud9qtd-aOI_7Bn/view?usp=sharing
2021-10-linkedin-com-patrick-iversen-649471b-img-1.jpg
https://drive.google.com/file/d/1PqRm4bJjLcsEOJT4ss-2rHwj9Q-RA4y5/view?usp=sharing
Knight Cancer Research Institute, OHSU
Member / June 2016 to Present
Oregon State University
Adjunct Professor ( Mar 2016 – Present / 5 yrs 8 mos / Location : Corvallis, Oregon )
My academic home is in the Department of Environmental & Molecular Toxicology in the College of Agriculture and have a joint appointment in the Department of Biochemistry and Biophysics in the College of Science. Research interests in the way endogenous and exogenous chemical exposures influence the flow of information from DNA to RNA to Protein which I refer to as "Central Dogma Disrupters." A related question involves management of emerging infectious disease with focus directed at environmental exposures that may lead to emergence of zoonotic viral infections.
[Sarepta Therapeutics (AVI BioPharma)] ( Total Duration : 18 yrs 10 mos )
Distinguished Scientist ( Jun 2012 – May 2016 / 4 yrs )
Integrated innovations in oligonucleotide induced exon inclusion for rare genetic disease with pharmacokinetics, toxicology, and bioinformatics.
Communicated key insights of oligonucleotide based therapeutics to the newly established Sarepta Therapeutics company structure.
Discovered innovative approaches to manipulate therapeutic splice variant inducing oligonucleotides.
Provide continuity for infectious disease programs I initiated while at AVI BioPharma
Sr VP Research and Innovation ( Aug 1997 – Jun 2012 / 14 yrs 11 mos )
Discovery and development of AVI-4126, led preclinical development, prepared and submitted IND, and directed first in man studies. Completed phase II study for prevention of coronary restenosis. Initiated “Rare Genetic Disease” program in polycystic kidney disease resulting in Phase Ib study in adult PKD patients.
Created the anti-infective program, screen 21 viral families and gram negative bacteria. Successful IND and Phase I programs for AVI-4020 for West Nile Virus, AVI-4065 for Hepatitis C Virus, AVI-7537 for Ebola Zaire, AVI-7288 for Marburgvirus, and Radiversen (AVI-7100) for Influenza A.
Initiated Eteplirsen (AVI-4658) program based on oligonucleotide induced exon skipping, direct preclinical program, prepare IND and first in man studies. NDA Advisory Committee April 26, 2016 for treatment of Duchenne Muscular Dystrophy.
Discovered oligonucleotide manipulation of pluripotent stem cells to create therapeutic cells. Advisor to BetaStem, a spin-off company based on discovery.
University of Nebraska Medical Center
Professor ( 1987 – 1997 / 10 yrs )
Cenersen (OL(1)p53) discovery team (inventor on 2 patents), prepare and submit first IND to FDA and coordinated first in man studies for systemic therapeutic oligonucleotide. Press conference including CNN International interview.
Chairman, Department of Pharmacology Graduate Committee and program
Member Leukemia Society of America Board of Directors and Nebraska Chapter
Co-creator of “Poly-FdUMP,” 3 patents; Successful commercialization award 2009
Co-founder of Lynx Therapeutics a spin-off of Applied Biosystems
Education
Education
- University of Utah
Degree Name : PhD / Biochemical Pharmacology and Toxicology ( 1979 – 1984 )
- University of Utah School of Medicine
Degree Name : Ph.D. / Biochemical Pharmacology and Toxicology ( 1979 – 1984 )
2021-10-25-ancestry-com-public-records-directories-patrick-lynn-iversen.pdf
Name : Patrick Lynn Iversen [Patrick L Iverson]
Birth Date : Apr 1955
Residence Date : 2015-2020
Address : 2145 Redcliff Cir / Grand Junction, Colorado, USA / 81507
Second Residence Date : 1986-1999
Second Address : 8226 Wilson Dr / Omaha, Nebraska, USA / 68127
Third Address : 5602 Lakeview Dr Apt A / Kirkland, Washington, USA / 98033
Fourth Address : 5902 NW Fair Oaks Pl / Corvallis, Oregon, USA / 97330
EVIDENCE TIMELINE
EVIDENCE TIMELINE
1992 (July 01)
1992 (July 01)
https://www.newspapers.com/image/671944187/?terms=%22Patrick%20Iversen%22&match=1
1992-07-01-the-alliance-nebraska-times-herald-pg-10
1992-07-01-the-alliance-nebraska-times-herald-pg-10-clip-cancer-treatment
1992 (August)
1992 (August)
https://www.newspapers.com/image/311672026/?terms=%22Patrick%20Iversen%22&match=1
1992-08-02-the-lincoln-nebraska-star-pg-6e
1992-08-02-the-lincoln-nebraska-star-pg-6e-clip-died
1994 (Jan 30)
1994 (Jan 30)
Pg F1 https://www.newspapers.com/image/199716008
1994-01-30-the-greenville-news-pg-f1
1994-01-30-the-greenville-news-pg-f1-clip-cancer-iversen
Pg F4 https://www.newspapers.com/image/199716170/?terms=%22Patrick%20Iversen%22&match=1
1994-01-30-the-greenville-news-pg-f4
1997 (Sep 01)
1997 (Sep 01)
https://www.newspapers.com/image/387248112/?terms=%22Patrick%20Iversen%22&match=1
1997-09-01-the-gazette-tmes-corvallis-oregon-pg-c3-clip-on-the-move-iversen.jpg
2001 (April 09)
2001 (April 09)
https://www.newspapers.com/image/388431275/?terms=%22Patrick%20Iversen%22&match=1
2001-04-09-the-gazette-tmes-corvallis-oregon-pg-a7
2001-04-09-the-gazette-tmes-corvallis-oregon-pg-a7-clip-iversen
2002 (March 24)
2002 (March 24)
E1 https://newspaperarchive.com/johnstown-tribune-democrat-mar-24-2002-p-44/
2002-03-24-the-johnstown-tribune-democrat-pg-e1
E4 https://newspaperarchive.com/johnstown-tribune-democrat-mar-24-2002-p-47/
2002-03-24-the-johnstown-tribune-democrat-pg-e4
2002-03-24-the-johnstown-tribune-democrat-pg-e1-clip-drugs-iversen
2002 (July 08) - Article about father Phil Iversen
2002 (July 08) - Article about father Phil Iversen
A6 https://newspaperarchive.com/kalispell-daily-inter-lake-jul-08-2002-p-6/
2002-07-08-daily-inter-lake-idaho-montana-pg-6.jpg
A7 https://newspaperarchive.com/kalispell-daily-inter-lake-jul-08-2002-p-7/
2002-07-08-daily-inter-lake-idaho-montana-pg-7.jpg
2002-07-08-daily-inter-lake-idaho-montana-pg-6-clip-iversen
2002 (Dec 17) - West Nile Search
2002 (Dec 17) - West Nile Search
https://www.newspapers.com/image/526243375/?terms=%22Patrick%20Iversen%22&match=1
2002-12-17-the-world-coos-bay-oregon-pg-a9
2002-12-17-the-world-coos-bay-oregon-pg-a9-clip-west-nile
2003 (May 27)
2003 (May 27)
https://www.newspapers.com/image/446962828/?terms=%22Patrick%20Iversen%22&match=1
2003-05-27-santa-maria-times-pg-a12
2003-05-27-santa-maria-times-pg-a12-clip-smart-bomb-cancer-sars
2003 (June 30)
2003 (June 30)
8B https://www.newspapers.com/image/198411147/?terms=%22Patrick%20Iversen%22&match=1
2003-06-30-the-oregon-statesman-journal-pg-8b
2003-06-30-the-oregon-statesman-journal-pg-8b-clip-antisense.jpg
7B https://www.newspapers.com/image/198411080
2003-06-30-the-oregon-statesman-journal-pg-7b
2003 (Sep 05)
2003 (Sep 05)
https://www.newspapers.com/image/387695681/?terms=%22Patrick%20Iversen%22&match=1
2003-09-05-the-gazette-tmes-corvallis-oregon-pg-a3
2003-09-05-the-gazette-tmes-corvallis-oregon-pg-a3-clip-avi-bio
2004 (Dec 28)
2004 (Dec 28)
2004-12-28-the-gazette-tmes-corvallis-oregon-pg-a2-clip-tech-firm.jpg
2005 (Jan 21)
2005 (Jan 21)
https://www.newspapers.com/image/383498450/?terms=%22Patrick%20Iversen%22&match=1
2005-01-21-the-gazette-tmes-corvallis-oregon-pg-a2
2005-01-21-the-gazette-tmes-corvallis-oregon-pg-a2-clip-avi-bio
2008 (May 04)
2008 (May 04)
https://newspaperarchive.com/galveston-daily-news-may-04-2008-p-17/
2008-05-04-2008-the-galveston-daily-news-pg-c1.jpg
2008-05-04-2008-the-galveston-daily-news-pg-c1-clip-sars
2010 (Aug 22) - USAMRIID Press Release : "Novel 'antisense' therapies protect primates from lethal Ebola and Marburg viruses"
2010 (Aug 22) - USAMRIID Press Release : "Novel 'antisense' therapies protect primates from lethal Ebola and Marburg viruses"
Peer-Reviewed Publication : US ARMY MEDICAL RESEARCH INSTITUTE OF INFECTIOUS DISEASES / Saved as PDF : [HI007Y][GDrive]
Mentioned : Sina A Bavari (born 1959) / Dr. Patrick Lynn Iversen (born 1955) / AVI BioPharma /
New studies show that treatments targeting specific viral genes protected monkeys infected with deadly Ebola or Marburg viruses. Furthermore, the animals were protected even when therapeutics were administered one hour after exposure—suggesting the approach holds promise for treating accidental infections in laboratory or hospital settings.
The research, which appears in today's online edition of the journal Nature Medicine, was conducted by the U.S. Army Medical Research Institute of Infectious Diseases in collaboration with [AVI BioPharma], a Washington-based biotechnology firm.
Working with a class of compounds known as antisense phosphorodiamidate morpholino oligomers, or PMOs, scientists first performed a series of studies with mouse and guinea pig models of Ebola to screen various chemical variations. They arrived at a therapy known as AVI-6002, which demonstrated a survival rate of better than 90 percent in animals treated either pre- or post-exposure.
Encouraged by these results, the team conducted "proof of concept" studies in which 9 rhesus monkeys were challenged with lethal Ebola virus. Treatment was initiated 30-60 minutes after exposure to the virus. In these studies, 5 of 8 monkeys survived, while the remaining animal was untreated. Further experiments, including a multiple-dose evaluation, also yielded promising results, with 3 of 5 monkeys surviving in each of the AVI-6002 treatment groups when they received a dose of 40 mg per kg of body weight.
According to first author Travis K. Warren of USAMRIID, antisense drugs are useful against viral diseases because they are designed to enter cells and eliminate viruses by preventing their replication. The drugs act by blocking critical viral genetic sequences, essentially giving the infected host time to mount an immune response and clear the virus.
Ebola and Marburg cause hemorrhagic fever with case fatality rates as high as 90 percent in humans. The viruses, which are infectious by aerosol (although more commonly spread through blood and bodily fluids of infected patients), are of concern both as global health threats and as potential agents of biological warfare or terrorism. Currently there are no available vaccines or therapies. Research on both viruses is conducted in Biosafety Level 4, or maximum containment, laboratories, where investigators wear positive-pressure "space suits" and breathe filtered air as they work.
The USAMRIID team next turned its attention to Marburg virus, again screening various compounds in mice and guinea pigs to select a candidate for further testing. They settled upon AVI-6003, a drug that consistently conferred a high degree of efficacy (better than 90 percent survival) in both models.
Investigators conducted two pilot studies in cynomolgus monkeys to assess the efficacy of AVI-6003 against lethal challenge with Marburg virus. As with the Ebola studies, treatments were initiated 30-60 minutes after infection. All 13 animals receiving AVI-6003 survived. Additional research provided important information about the optimal therapeutic dose range of the compound, with a 40 mg per kg body weight dose protecting 100 percent of the monkeys following challenge.
"This report of successful early post-exposure treatment of filovirus hemorrhagic fever is significant on its own," said Colonel John P. Skvorak, USAMRIID commander, "but the drug characteristics of these PMOs also support investigation of potentially broader therapeutic applications."
Senior author [ Sina A Bavari (born 1959)] said USAMRIID has been collaborating with AVI BioPharma since 2004. In February of that year, an Institute scientist working in a Biosafety Level 4 laboratory stuck her thumb with a needle while treating Ebola-infected mice with antibodies. As a precaution, USAMRIID medical experts recommended the investigator be isolated for 21 days to ensure that she had not been infected.
Coincidentally, earlier that very day, [Dr. Patrick Lynn Iversen (born 1955)] from AVI BioPharma had presented a seminar at USAMRIID concerning the efficacy of novel antisense drugs against a range of viruses. When he found out that a USAMRIID scientist had potentially been exposed to Ebola virus, the company volunteered to design and synthesize compounds against the virus to treat her if the need arose.
The team at AVI worked for four straight days to generate human-grade anti-Ebola compounds. In the meantime, their regulatory staff worked with USAMRIID physicians to gain emergency approval from the U.S. Food and Drug Administration to use the compounds if necessary. Five days after the exposure, AVI delivered the compounds to USAMRIID's medical team.
Fortunately, the scientist had escaped infection with Ebola virus, so the compounds were never used. However, USAMRIID went on to test them in animal models, and has been collaborating with AVI ever since.
According to the authors, the investigational new drug applications (IND) for AVI-6002 and AVI-6003 have been submitted to the U.S. Food and Drug Administration, and they are now open to proceed with clinical trials.
NOTES:
- Collaborating on the study were Travis K. Warren, Jay Wells, Kelly S. Donner, Sean A. Van Tongeren, Nicole L. Garza, Donald K. Nichols, Lian Dong, and Sina Bavari of USAMRIID; Kelly L. Warfield and Dana L. Swenson, formerly of USAMRIID; and Dan V. Mourich, Stacy Crumley, and Patrick L. Iversen of AVI BioPharma.
- USAMRIID, located at Fort Detrick, Maryland, is the lead medical research laboratory for the U.S. Department of Defense Biological Defense Research Program, and plays a key role in national defense and in infectious disease research. The Institute's mission is to conduct basic and applied research on biological threats resulting in medical solutions (such as vaccines, drugs and diagnostics) to protect the warfighter. USAMRIID is a subordinate laboratory of the U.S. Army Medical Research and Materiel Command.
- Reference: Travis K. Warren, Kelly L. Warfield, Jay Wells, Dana L. Swenson, Kelly S. Donner, Sean A. Van Tongeren, Nicole L. Garza, Lian Dong, Dan V. Mourich, Stacy Crumley, Donald K. Nichols, Patrick L. Iversen and Sina Bavari; "Advanced antisense therapies for postexposure protection against lethal filovirus infections," Nature Medicine (22 August 2010).
2011 (March) - Co-Presenting with Kincaid
2011 (March) - Co-Presenting with Kincaid
https://www.grc.org/chemical-and-biological-terrorism-defense-conference/2011/
2012 (Dec) -
Discovery and Early Development of AVI-7537 and AVI-7288 for the Treatment of Ebola Virus and Marburg Virus Infections
Discovery and Early Development of AVI-7537 and AVI-7288 for the Treatment of Ebola Virus and Marburg Virus Infections
December 2012
Viruses 4(11):2806-30
DOI:10.3390/v4112806
Source
Authors:
Hide
There are no currently approved treatments for filovirus infections. In this study we report the discovery process which led to the development of antisense Phosphorodiamidate Morpholino Oligomers (PMOs) AVI-6002 (composed of AVI-7357 and AVI-7539) and AVI-6003 (composed of AVI-7287 and AVI-7288) targeting Ebola virus and Marburg virus respectively. The discovery process involved identification of optimal transcript binding sites for PMO based RNA-therapeutics followed by screening for effective viral gene target in mouse and guinea pig models utilizing adapted viral isolates. An evolution of chemical modifications were tested, beginning with simple Phosphorodiamidate Morpholino Oligomers (PMO) transitioning to cell penetrating peptide conjugated PMOs (PPMO) and ending with PMOplus containing a limited number of positively charged linkages in the PMO structure. The initial lead compounds were combinations of two agents targeting separate genes. In the final analysis, a single agent for treatment of each virus was selected, AVI-7537 targeting the VP24 gene of Ebola virus and AVI-7288 targeting NP of Marburg virus, and are now progressing into late stage clinical development as the optimal therapeutic candidates.
2014 (March ) -
2014 (March ) -
Induced IL-10 Splice Altering Approach to Antiviral Drug Discovery
Induced IL-10 Splice Altering Approach to Antiviral Drug Discovery
March 2014
Source
Authors:
U.S. Forest Service
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Ebola virus causes an acute hemorrhagic fever lethal in primates and rodents. The contribution of host immune factors to pathogenesis has yet to be determined and may reveal efficacious targets for potential treatment. In this study, we show that the interleukin (IL)-10 signaling pathway modulates Ebola pathogenesis. IL-10(-/-) mice and wild-type mice receiving antisense targeting IL-10 signaling via disrupting expression through aberrant splice altering were resistant to ebola virus infection. IL-10(-/-) mice exhibited reduced viral titers, pathology, and levels of IL-2, IL-6, keratinocyte-derived chemokine (KC), and macrophage inflammatory protein-1 α and increased interferon (IFN)-γ relative to infected wild-type mice. Furthermore, antibody depletion studies in IL-10(-/-) mice suggest a requirement for natural killer cells and IFN-γ for protection. Together, these data demonstrate that resistance to ebola infection is regulated by IL-10 and can be targeted in a prophylactic manner to protect against lethal hemorrhagic virus challenge.
2014 (Oct)
Viral diversity and clonal evolution from unphased genomic data
Viral diversity and clonal evolution from unphased genomic data
October 2014
BMC Genomics 15(Suppl 6):S17
DOI:10.1186/1471-2164-15-S6-S17
Source
Authors:
Institut de Recherche Biomédicale des Armées
Clonal expansion is a process in which a single organism reproduces asexually, giving rise to a diversifying population. It is pervasive in nature, from within-host pathogen evolution to emergent infectious disease outbreaks. Standard phylogenetic tools rely on full-length genomes of individual pathogens or population consensus sequences (phased genotypes). We introduce two measures of diversity to study the evolution of clonal populations using unphased genomic data, which eliminate the need to construct full-length genomes. Our method follows a maximum likelihood approach to estimate evolutionary rates and times to the most recent common ancestor, based on a relaxed molecular clock model; independent of a growth model. Deviations from neutral evolution indicate the presence of selection and bottleneck events. We evaluated our methods in silico and then compared it against existing approaches with the well-characterized 2009 H1N1 influenza pandemic. We then applied our method to high-throughput genomic data from marburgvirus-infected non-human primates and inferred the time of infection and the intra-host evolutionary rate, and identified purifying selection in viral populations. Our method has the power to make use of minor variants present in less than 1% of the population and capture genomic diversification within days of infection, making it an ideal tool for the study of acute RNA viral infection dynamics.
2014 (Nov 16)
2014 (Nov 16)
2016-11-16-albany-democrat-herald-pg-a1
2016-11-16-albany-democrat-herald-pg-a1-clip-ebola.jpg
https://www.newspapers.com/image/631404870/
2016-11-16-albany-democrat-herald-pg-a4
https://www.newspapers.com/image/631404877
2016-11-16-albany-democrat-herald-pg-a5
https://www.newspapers.com/image/631404857/?terms=%22Patrick%20Iversen%22&match=1
2015 (Feb)
ArticlePDF Available
A Single Phosphorodiamidate Morpholino Oligomer Targeting VP24 Protects Rhesus Monkeys against Lethal Ebola Virus Infection
A Single Phosphorodiamidate Morpholino Oligomer Targeting VP24 Protects Rhesus Monkeys against Lethal Ebola Virus Infection
February 2015
mBio 6(1)
Source
Authors:
Ebola viruses (EBOV) cause severe disease in humans and nonhuman primates with high mortality rates and continue to emerge in new geographic locations, including several countries in West Africa, the site of a large ongoing outbreak. Phosphorodiamidate morpholino oligomers (PMOs) are synthetic antisense molecules that are able to target mRNAs in a sequence-specific fashion and suppress translation through steric hindrance. We previously showed that the use of PMOs targeting a combination of VP35 and VP24 protected rhesus monkeys from lethal EBOV infection. Surprisingly, the present study revealed that a PMOplus compound targeting VP24 alone was sufficient to confer protection from lethal EBOV infection but that a PMOplus targeting VP35 alone resulted in no protection. This study further substantiates recent data demonstrating that VP24 may be a key virulence factor encoded by EBOV and suggests that VP24 is a promising target for the development of effective anti-EBOV countermeasures. Several West African countries are currently being ravaged by an outbreak of Ebola virus (EBOV) that has become a major epidemic affecting not only these African countries but also Europe and the United States. A better understanding of the mechanism of virulence of EBOV is important for the development of effective treatments, as no licensed treatments or vaccines for EBOV disease are currently available. This study of phosphorodiamidate morpholino oligomers (PMOs) targeting the mRNAs of two different EBOV proteins, alone and in combination, demonstrated that targeting a single protein was effective at conferring a significant survival benefit in an EBOV lethal primate model. Future development of PMOs with efficacy against EBOV will be simplified if only one PMO is required instead of a combination, particularly in terms of regulatory approval. Copyright © 2015 Warren et al.
2015 (July) - With Warfield and Bavari
AVI-7288 for Marburg Virus in Nonhuman Primates and Humans
AVI-7288 for Marburg Virus in Nonhuman Primates and Humans
July 2015
New England Journal of Medicine 373(4):339-48
Source
Project: Hemorrhagic fever
Authors:
This person is not on ResearchGate, or hasn't claimed this research yet.
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AVI-7288 is a phosphorodiamidate morpholino oligomer with positive charges that targets the viral messenger RNA that encodes Marburg virus (MARV) nucleoprotein. Its safety in humans is undetermined. We assessed the efficacy of AVI-7288 in a series of studies involving a lethal challenge with MARV in nonhuman primates. The safety of AVI-7288 was evaluated in a randomized, multiple-ascending-dose study in which 40 healthy humans (8 humans per dose group) received 14 once-daily infusions of AVI-7288 (1 mg, 4 mg, 8 mg, 12 mg, or 16 mg per kilogram of body weight) or placebo, in a 3:1 ratio. We estimated the protective dose in humans by comparing pharmacokinetic variables in infected nonhuman primates, uninfected nonhuman primates, and uninfected humans. Survival in infected nonhuman primates was dose-dependent, with survival rates of 0%, 30%, 59%, 87%, 100%, and 100% among monkeys treated with 0 mg, 3.75 mg, 7.5 mg, 15 mg, 20 mg, and 30 mg of AVI-7288 per kilogram, respectively (P<0.001 with the use of the log-rank test for the comparison of survival across groups). No safety concern was identified at doses up to 16 mg per kilogram per day in humans. No serious adverse events were reported. Drug exposure (the area under the curve) was dose-dependent in both nonhuman primates and humans; drug clearance was independent of dose but was higher in nonhuman primates than in humans. The protective dose in humans was initially estimated, on the basis of exposure, to be 9.6 mg per kilogram per day (95% confidence interval, 6.6 to 12.5) for 14 days. Monte Carlo simulations supported a dose of 11 mg per kilogram per day to match the geometric mean protective exposure in nonhuman primates. This study shows that, on the basis of efficacy in nonhuman primates and pharmacokinetic data in humans, AVI-7288 has potential as postexposure prophylaxis for MARV infection in humans. (Funded by the Department of Defense; ClinicalTrials.gov number, NCT01566877.).
2016 (Feb) - Research (with Sina Bavari)
https://www.researchgate.net/publication/295682568_Delayed_Time-to-Treatment_of_an_Antisense_Morpholino_Oligomer_Is_Effective_against_Lethal_Marburg_Virus_Infection_in_Cynomolgus_Macaques
Delayed Time-to-Treatment of an Antisense Morpholino Oligomer Is Effective against Lethal Marburg Virus Infection in Cynomolgus Macaques
Delayed Time-to-Treatment of an Antisense Morpholino Oligomer Is Effective against Lethal Marburg Virus Infection in Cynomolgus Macaques
February 2016
PLoS Neglected Tropical Diseases 10(2):e0004456
DOI:10.1371/journal.pntd.0004456
Authors:
Institut de Recherche Biomédicale des Armées
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Abstract and Figures
Abstract and Figures
Marburg virus (MARV) is an Ebola-like virus in the family Filovirdae that causes sporadic outbreaks of severe hemorrhagic fever with a case fatality rate as high as 90%. AVI-7288, a positively charged antisense phosphorodiamidate morpholino oligomer (PMOplus) targeting the viral nucleoprotein gene, was evaluated as a potential therapeutic intervention for MARV infection following delayed treatment of 1, 24, 48, and 96 h post-infection (PI) in a nonhuman primate lethal challenge model. A total of 30 cynomolgus macaques were divided into 5 groups of 6 and infected with 1,830 plaque forming units of MARV subcutaneously. AVI-7288 was administered by bolus infusion daily for 14 days at 15 mg/kg body weight. Survival was the primary endpoint of the study. While none (0 of 6) of the saline group survived, 83-100% of infected monkeys survived when treatment was initiated 1, 24, 48, or 96 h post-infection (PI). The antisense treatment also reduced serum viremia and inflammatory cytokines in all treatment groups compared to vehicle controls. The antibody immune response to virus was preserved and tissue viral antigen was cleared in AVI-7288 treated animals. These data show that AVI-7288 protects NHPs against an otherwise lethal MARV infection when treatment is initiated up to 96 h PI.
2016 (Sep 29)
2016 (Sep 29)
https://www.newspapers.com/image/767412042/?terms=%22Patrick%20Iversen%22&match=1
2016-09-29-albany-democrat-herald-pg-a4-clip-drug-hope.jpg
COMMENT| VOLUME 20, ISSUE 6, P636-637, JUNE 01, 2020
https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30065-7/fulltext
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Chimpanzee adenovirus type 3 vectored Ebola vaccine: expanding the field
Sina Bavari
Patrick L Iversen
Published:March 19, 2020DOI:https://doi.org/10.1016/S1473-3099(20)30065-7
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In 2019, Ervebo, the rVSV-ZEBOV vaccine3 for the prevention of Ebola virus disease in individuals aged 18 years and older was approved by regulators in the USA and Europe. The question of how dozens of Ebola vaccines using various platforms (eg, vectored, DNA, RNA, antigen presentation vaccines)4 will be implemented in the wake of rVSV-ZEBOV approval needs to be further considered as most vaccines are not expected to show equivalence or superiority to rVSV-ZEBOV. The PREVAIL study revealed anti-glycoprotein Ebola virus immunoglobulin (Ig)G concentrations were higher 1 month post vaccination with rVSV-ZEBOV compared with ChAd3-EBO-Z.5 Although rVSV-ZEBOV, was safe and immunogenic in children and adolescents, shedding of the vaccine was observed in saliva and urine. The present outbreak in the Democratic Republic of the Congo, in which approximately 29% of cases are in children aged younger than 18 years, has a case fatality rate of up to 80%. The current reports support the potential use of ChAd3-EBO-Z in individuals aged younger than 18 years.
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The ChAd3-EBO-Z vaccine was protective in a non-human primate model, which is the most direct evidence of vaccine efficacy.6 Predictive comparisons between non-human primate observations and human responses to vaccines are essential but limited because of the high viral titre in the non-human primate challenge and variations in the T-cell receptor subtypes. Phase 1 studies indicated acceptable safety and reactogenicity, but transient decreases in thrombocyte counts were regarded as a potential safety signal requiring further assessment in these phase 2 studies. The secondary endpoint in each trial included evaluation of anti-glycoprotein antibody titres before and 30 days after vaccination. A control with ChAd3 empty vector rather than phosphate buffered saline versus ChAd3-EBO-Z would be more appropriate, but it is understandable that trials should be streamlined so that the number of different cohorts is as small as possible. Determination of pre-existing immunity to the ChAd3 component might have been helpful in the interpretation of observations. Vaccine associated T-cell responses were of low amplitude and neutralising antibody responses are a small proportion of total IgG to Ebola virus glycoprotein. These data suggest the vaccine might be adequate as a component in a prime boost strategy but more robust and durable responses are required to control epidemics from single vaccination protocols. Greater consideration of how genetic makeup, environmental factors, microflora composition, co-infection with measles, HIV, or malaria, and nutritional status influence antibody responses are needed to explore observations of lower anti-glycoprotein responses in Senegalese volunteers compared with UK volunteers. Substantial future research is required to seek an optimal vaccine for further boosting of the immune response, interval between prime and boost, and vaccine doses, as well as improved correlates of immune protection.
In the trials described by Tapia, exclusion criteria included no previous vaccination to Ebola virus, no contact with a person with Ebola virus disease in 30 days, and no previous infection with Sudan Ebola virus. However, pre-existing anti-glycoprotein antibody titres were observed in high numbers of healthy adult participants (25%) and healthy children aged 1–5 years (12%), 6–12 years (12%), and 13–17 years (28%). The lower pre-existing antibody titres in young children than adults might address concerns for the ELISA method in that lower titres can be detected. The appearance of pre-existing antibody titres points to possible asymptomatic and endemic infections, which has been previously reported.7, 8 However, the current reports point to a greater prevalence, 25% versus 3–11%, which might reflect the variability in the study population exposure or assay methods and in both cases, the participant requires further evaluation. Whether participants who are pre-exposed should be separated in analysis as vaccine booster participants should be a consideration for future exclusion criteria in subsequent vaccine trials.
Cell-mediated immunity induced by the vaccine decreased with age in children. Cell-mediated immunity was low at 6 months after vaccination and observation of it in the adult placebo group deserves more attention. The order of vaccination in the study in children revealed a diminished response to the ChAd3 vaccine if administered after the MenACWY-TT vaccine. Measurement of MenACWY-TT vaccine responses in the presence of ChAd3 could help to further expand our understanding of immune responses to these vaccines. Previous or concurrent infections with malaria, measles, HIV, or tuberculosis (and other infections) could contribute substantially to variations in vaccine response and efficacy. Enhanced neutralising antibody combined with robust cell-mediated immunity responses could allow development of more efficacious vaccines. A deeper understanding of protective correlates and enhanced durability might allow better interpretation of vaccine efficacy. Without such data, questions could arise regarding the advisability of creating a multivalent vaccine for filoviruses.
OMMENT| VOLUME 21, ISSUE 6, P746-748, JUNE 01, 2021
https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00020-7/fulltext
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Inactivated COVID-19 vaccines to make a global impact
Patrick L Iversen
Sina Bavari
Published:February 03, 2021DOI:https://doi.org/10.1016/S1473-3099(21)00020-7
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Many inactivated vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being tested at various clinical stages. Most of these vaccines are formulated with aluminium hydroxide, and one, VLA-2001, has two adjuvants, CpG oligodeoxynucleotides and aluminium hydroxide.1, 2 Because of the ease of production and scale-up and relatively low cost, inactivated vaccines can capture a sizeable portion of the SARS-CoV-2 vaccine landscape. Inactivated vaccines are well established and can provide advantages in a variety of distinct populations, including those with degrees of immune senescence. Given that the risk of more severe COVID-19 increases with age, the clinical evaluation of the responses of older adults to vaccines is essential.3
In The Lancet Infectious Diseases, Zhiwei Wu and colleagues4 report the results of a randomised, double-blind, placebo-controlled phase 1/2 clinical trial evaluating an inactivated COVID-19 vaccine, CoronaVac, in healthy adults aged 60 years and older (72 in phase 1 and 350 in phase 2). The aluminium hydroxide-adjuvanted vaccine was given as two injections (days 0 and 28), and three different doses were tested (1·5 μg, 3 μg, and 6 μg per injection). The vaccine showed good safety and tolerability; adverse reactions, the most frequent being injection site pain (39 [9%] of 421 participants), were all mild or moderate in severity and no serious adverse events related to vaccination were recorded. Neutralising antibody titres were measured for all doses 28 days after the second injection. Because similar responses were seen with doses of 3 μg (seroconversion rate 98·0% [95% CI 92·8–99·8]) and 6 μg (99·0% [94·5–100·0]) in phase 2, and these doses elicited better responses than did the 1·5 μg dose, the authors proposed the use of a 3 μg dose in the phase 3 trial. This report is a companion to an earlier report of the safety and immunogenicity of CoronaVac in adults aged 18–59 years.5
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Several limitations were acknowledged in this report, which are consistent with rapid-fire trials executed during the pandemic. The durability of immune response and latent adverse effects were not evaluated during the 2 month period. All participants were of Han Chinese ethnicity, and greater ethnic diversity in populations will be examined in the phase 3 trials. The 4 week interval from prime to boost might not be optimal, and no measures of T-cell or cytokine responses were included. However, these reported limitations represent a veneer of deeper issues capable of shaking confidence in vaccine utility in an ageing population.
Correlates of immune protection have not been established for SARS-CoV-2 vaccines to date, posing a foundational constraint to any vaccine development, although many vaccines have been granted emergency use approvals around the globe. Comparisons of various vaccine platforms have been hampered because, until recently, there were no standard pooled convalescent sera from infected individuals to use as a reference standard.6 Interpretation of immune responses is limited in that no consensus standard methods for measuring neutralising antibody titres are in place, thereby confounding comparisons between age groups and comparisons with different vaccine strategies.
Immune senescence is complex and there are no validated methods to identify early stages or measures of severity.7 A correlation between anti-receptor-binding domain IgG and neutralising antibodies has been reported for adults aged 18–59 years,5 but this relationship might not hold true for older individuals with various stages of immune senescence. A similar relationship between T-cell responses and IFN-γ observed in adults might not exist in immune-senescent individuals. We encourage measurement of comparable immune features in future studies of individuals aged 18–59 years or 60 years and older. A diminished T-cell response in an older population is anticipated, but a possible reduction in neutralising antibody titre in people older than 70 years has not been fully studied. We encourage a granular evaluation of age groups to permit identification of age-related limitations in vaccine utility. IgM or the transition to IgG were not reported in Wu and colleagues' study,4 so the integrity of B-cell function is not known. In general, it might be safe to proceed, but adjustments in dose and the interval between prime and boost in the population aged 60 years and older might be necessary, based on the measures from this study.
100 million people will soon have recovered from SARS-CoV-2 infection. Most recovered individuals have had antibody and T-cell responses against multiple SARS-CoV-2 proteins, but vaccination of these individuals might be necessary to prevent reinfection. Compared with other vaccines targeting only the spike protein, inactivated vaccines could provide an added benefit to these individuals by boosting their T-cell responses against many of the SARS-CoV-2 proteins.
Advancements in the development of an inactivated vaccine provide additional opportunities, but the pace of development must be balanced with quantitative measures of safety and efficacy. Inclusion of additional viral antigens in the inactivated vaccine could provide efficacy over time and as variants emerge. However, shifting viral antigens could also predispose an inactivated vaccine to causing antibody-dependent enhancement of disease.8 It is important to create a vaccine portfolio composed of different strategies for a more robust defence against the SARS-CoV-2 pandemic.
We declare no competing interests.
COMMENT| VOLUME 21, ISSUE 8, P1054-1055, AUGUST 01, 2021
https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00149-3/fulltext
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Is there space for a three-dose vaccine to fight the spread of SARS-CoV-2?
Patrick L Iversen
Sina Bavari
Published:March 24, 2021DOI:https://doi.org/10.1016/S1473-3099(21)00149-3
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The ongoing responses to the COVID-19 pandemic have resulted in diverse vaccine-based solutions that are advancing our understanding of medical science.1 Randomised, placebo-controlled clinical trials are providing a unique opportunity to compare the safety and immunogenicity of several different vaccine platforms, including vectored, DNA, inactivated virus, mRNA, and protein subunit vaccines. Strategic differences within each vaccine platform, such as dimer versus trimer protein subunits or modifications in protein design based on dynamic structural modelling, are providing deeper insights into the optimal vaccines of the future—a silver lining to the dark cloud of the COVID-19 pandemic.
In The Lancet Infectious Diseases, Shilong Yang and colleagues2 report the results of two randomised, double-blind, placebo-controlled, phase 1 and 2 trials of ZF2001, a protein subunit vaccine combined with alum as an adjuvant. The key findings from these two trials are that this receptor-binding domain (RBD)-protein subunit vaccine is safe and immunogenic in healthy adults. The use of a dimeric protein rather than native trimer RBD reveals novel insights into the immunogenicity requirements for a COVID-19 vaccine. The combination of a protein subunit and alum adjuvant is expected to generate limited efficacy, which might explain the three-dose regimen and relatively high dose of protein subunit. However, is a COVID-19 vaccine that requires three doses feasible and practical during the ongoing pandemic? The 25 μg and 50 μg doses are relatively high when compared to other protein subunit vaccines, and some immune markers of efficacy such as the IgG titre to the RBD target and the 50% neutralisation titre were lower with the 50 μg dose than with the 25 μg dose. Hence, the dose selection is not compelling and more studies are required to investigate the optimal dose and time regimen for the ZF2001 vaccine. The immunological correlates of protection are not well defined for SARS-CoV-2. Hence, limited measures of IgG and neutralisation titres offer only a glimpse and little guidance for the selection of a sufficiently effective vaccine. Protection from SARS-CoV-2 infection appears to be elicited as early as 9–11 days after the initial vaccination.3, 4 This protection is offered when neutralising antibodies are barely detectable or in limited supply. We recommend more measures of immune response that might provide insights into functional antibody immune responses, such as Fab and Fc-effector functions.5 A deeper understanding of how various vaccines and adjuvants can broaden these effector functions could clarify ways to extend vaccine efficacy. Finally, at present there is no evidence to suggest that the design and use of a dimer protein will retain protection against the emerging SARS CoV-2 variants. Overall, the silver lining of scientific insight into optimal vaccines for COVID-19 could be substantially brighter.
A recent phase 1 clinical study using the spike-Trimer (SCB-2019) vaccine in combination with various adjuvants demonstrated that the spike-Trimer vaccine elicits high neutralising activity at a dose as low as 3 μg per injection of vaccine, quickly after the second vaccine dose.6 These data suggest that the use of trimerised spike protein as a vaccine might have some advantages over other forms of spike proteins, but side-by-side clinical studies are required to determine the best vaccine protein and adjuvants.
The state of the current vaccine landscape continues to raise the bar for vaccine candidates. At present, it is unclear whether the use of a three-dose regimen (prime, boost, boost) in a limited timespan for the ZF2001 protein subunit vaccine will offset the benefits of the less demanding storage conditions that limit RNA vaccines. As new SARS-CoV-2 variants emerge, the optimal COVID-19 vaccine should provide broad-spectrum coverage, which might be possible with an engineered spike-protein subunit vaccine comprising a more robust adjuvant. At some point, despite the good intentions to develop a COVID-19 vaccine suitable for global use, less effective vaccines could face ethical scrutiny. If future studies of ZF2001 fall short of the high efficacy milestones seen with the other vaccines developed so far, will people be satisfied with the reduced efficacy?
2021 (August)
https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(21)00205-1/fulltext
COMMENT| VOLUME 2, ISSUE 9, E529-E530, SEPTEMBER 01, 2021
Extending the interval of COVID-19 vaccine regimens in individuals aged 80 years or older
Extending the interval of COVID-19 vaccine regimens in individuals aged 80 years or older
Extending the interval of COVID-19 vaccine regimens in individuals aged 80 years or older
Open AccessPublished:August 19, 2021DOI:https://doi.org/10.1016/S2666-7568(21)00205-1
More than 100 SARS-CoV-2 vaccines are in clinical and preclinical research stages,1 and some are approaching full approval by regulatory bodies. Lessons from the COVID-19 pandemic continue to extend our understanding of vaccine biology. Age-specific mortality from and immunity to SARS-CoV-2 infection have emphasised the vulnerability of older adults to COVID-19 and the higher case fatality in this population compared with younger people.2 To achieve optimum efficacy, most of the advanced SARS-CoV-2 vaccines must be given in two doses,1 although some, such as the BNT162b2 mRNA vaccine (tozinameran; developed by Pfizer–BioNTech) and the ChAdOx1 nCoV-19 adenovirus-vector vaccine (Oxford University–AstraZeneca), have shown efficacy after the first dose.3, 4 These findings were obtained from studies done in younger individuals, and attempts to expand them into groups aged 80 years or older have been lacking. Increasing the interval between the first and second doses of the vaccine can help to stretch vaccine supplies; however, implementing such regimens should be based on a firm understanding of the immune responses and efficacy in the most vulnerable populations. Further exploration of human immune senescence in people aged 80 years or older should be adequately addressed to allow better monitoring of this group's immune responses to SARS-CoV-2 vaccines.
In two Articles in The Lancet Healthy Longevity, Helen Parry and colleagues5 and Gokhan Tut and colleagues,6 as part of the Paul Moss research group at the University of Birmingham, report on their investigations of the immunogenicity of a single dose of the BNT162b2 or ChAdOx1 nCoV-19 vaccines in individuals aged 80 years or older.5, 6 In the complementary Articles, immune responses were explored in people aged 80 years or older living independently (n=165), and in residents (n=35; median age 87 years [IQR 77–90]) and staff (n=89; 48 years [35·5–56]) of long-term care facilities (LTCFs). Encouragingly, single doses of either the BNT162b2 or ChAdOx1 nCoV-19 vaccine reliably elicited humoral immunity in older people in both studies. In Tut and colleagues' study,6 humoral immune responses to the vaccines in participants without serological evidence of previous SARS-CoV-2 infection were slower to peak in LTCF residents than in LTCF staff, with the apparent correlation between age and spike-specific IgG antibody titre disappearing only in the subset of samples taken more than 42 days since vaccination. The effect of the slow increase in spike-specific antibodies in this population should be further investigated.
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Additionally, Tut and colleagues' study provided a preliminary indication of the diminished responses of older people to some of the circulating SARS-CoV-2 variants, and should alert us to the possibility that the slow kinetics of responses to vaccines in this population might hinder the protection of such individuals against future variants of SARS-CoV-2. The use of adjuvants to more rapidly and fully stimulate humoral immune responses in older people might help efforts to protect this population.
The two studies also examined cellular immune responses to the vaccines. Cellular immune responses were weaker and slower to develop than humoral immunity and positive spike-specific T-cell responses were found only in a small subset of vaccinated individuals in both studies, although those with evidence of previous SARS-CoV-2 infection in Tut and colleagues' study all showed positive T-cell responses. At 5–6 weeks post vaccination, the ChAdOx1 nCoV-19 vaccine induced a higher level of cellular responses than did the BNT162b2 vaccine.5
These Articles address a crucial concern regarding the interval between the first and second doses of vaccine in older people. Extending the vaccine interval permits the acceleration of vaccine population coverage during the pandemic. The findings might support extending the interval to up to 7 weeks in individuals aged 80 years and older.
Evidence of previous natural infection with SARS-CoV-2 was found in 12 (34%) of 35 residents of LTCFs,6 suggesting the possibility of bias in this population and limiting the generalisability of the results to people living independently, in whom rates of previous infection differ. A single dose of vaccine is effectively a booster in people who have previously been infected, and both antibody titres and cellular immunity were significantly higher in such individuals. Additionally, randomisation and group sizes represent a significant challenge in conducting studies in individuals aged 80 years and older, which limits the significance of study conclusions. Another limitation of the study is the measure of functional immune responses to vaccination; functional humoral responses and correlates of immune protection are not fully understood for vaccination in all age groups. However, given the greater fatality rate of SARS-CoV-2 infection in people aged 80 years and older, and the proximity of this age to average life expectancy, a simple follow-up measure of greater duration of survival might provide insight into a functional immune response in vaccinated individuals.
Perhaps the most surprising finding in Tut and colleague's study was the levelling effect of previous infection on the overall immune responses of older versus younger participants. Older participants with serological evidence of previous SARS-CoV-2 infection had robust immune responses to the vaccine and their antibodies were of higher concentration and perhaps greater functionality for neutralising the virus compared with older people who had not previously been infected. These data further support the importance of vaccination in people with previous exposure to SARS-CoV-2 and suggest further expansion of the immune response can occur in older adults who were previously infected. Further studies should aim to enhance our understanding of how the timing of vaccination post infection could benefit older adults.
The influence of SARS CoV-2 variants of concern on vaccine protection has been actively evaluated in younger populations. The observation that antibody inhibition of spike–ACE2 binding by the B.1.351 (beta) and P.1 (gamma) variants of concern were low in samples from older adults without evidence of previous infection in Tut and colleagues' study is of keen interest,6 and suggests that the limitations of vaccine protection against variants of concern might be substantial in this population, especially considering the modest cellular immune response elicited by a single dose of vaccine in this group. Exactly how extended-interval dosing might protect against future variants of concern is an important consideration and additional studies could help to better define dose regimens in people aged 80 years and older. Collectively, these observations highlight the potential greater vulnerability of vaccinated older adults to infection by variants of concern compared with younger people.
We declare no competing interests.
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