Anna Durbin, MD Professor of Medicine & Public Health Kawsar - PowerPoint PPT Presentation

Anna Durbin, MD Professor of Medicine & Public Health Kawsar Talaat, MD Assistant Professor of Medicine & Public Health Johns Hopkins Vaccine Initiative, Center for Immunization Research

Drs. Chida, Durbin, Melia, and Talaat have no relevant disclosures

Clinical Case • 18 year old female who presented 2 day history of high fever (39 – 40.2), severe headache, abdominal pain, and rash. • Rash was located on distal upper and lower extremities and was petechial • Pneumonia evident on CXR • Found to have atypical measles • Had been vaccinated as a child with 3 doses of formalin inactivated measles vaccine

Atypical measles Temperature Duration Pneum • Occurred years after initial vaccination (days) onia Age Sex MAX. Rash Edema with formalin inactivated measles 6 F 40.6 7 M,V,P + RML vaccine 6 M 39.4 7 M,P + ? • 3 doses given 1 month apart 7 F 40.0 7 M,V,P + B+E • Rash began on the distal extremities and concentrated on the ankles, wrists, 7 F 40.6 7 M,P + RLL+E and creases 6 M 40.0 5 M,P 0 B • High fever, severe headache, severe 6 F 40.0 5 M,V,P + RML abdominal pain, often vomiting 8 F 40.6 4 M 0 RML • 15 – 60% of immunized children 6 M 40.6 6 M,P 0 B+E subsequently exposed to wild-type 7 F 39.4 4 M,V + RLL measles virus developed atypical 8 F 40.6 5 M + RLL measles

Immune pathogenesis • Immune enhancement of disease has been documented with formalin inactivated measles and RSV vaccines. • The vaccines induced antibodies however the protection was transient • Secondary exposure to wildtype measles led to a CD4 response with a Th2 bias • Eosinophilic and neutrophilic infiltrates found in the lungs • Immune complex deposition in the lungs

Why We Need a SARS-Cov-2 Vaccine

Where Things Stand with Herd Immunity https://www.nytimes.com/interactive/2020/05/28/upshot/coronavirus-herd- immunity.html?action=click&module=Well&pgtype=Homepage&section=The%20Upshot. Accessed 29 May 2020.

Lessons from 1918 Influenza Pandemic • Study of weekly pneumonia and influenza mortality data for 43 US cities. • 1920, combined population of approximately 22% of the total US population • Nonpharmaceutical interventions grouped into 3 major categories: school closure; public gathering bans; and isolation and quarantine Markle H, et al. JAMA. 2007 Aug 8;298(6):644-54. doi: 10.1001/jama.298.6.644.

Timing Markle H, et al. JAMA. 2007 Aug 8;298(6):644-54. doi: 10.1001/jama.298.6.644.

Length of Intervention Markle H, et al. JAMA. 2007 Aug 8;298(6):644-54. doi: 10.1001/jama.298.6.644.

Length of Intervention Markle H, et al. JAMA. 2007 Aug 8;298(6):644-54. doi: 10.1001/jama.298.6.644.

Lessons from 1918 Influenza Pandemic • Cities implementing multiple interventions early → peak death rates ~50% lower than those that did not • Death rates climbed after interventions were lifted • For these “second waves:” inverse correlation of height of first and second peak weekly mortality rates • Cities with low first wave peaks at greater risk of large second wave • These low first wave peak cities experienced second waves sooner • ~6-8w after the first peak vs. 10-14w for cities with higher first peak mortality rates • No city experienced a second wave with main NPI battery in place Hatchett RJ et al. Proc Natl Acad Sci U S A. 2007 May 1;104(18):7582-7.

Lessons from 1918 Influenza Pandemic Weeks 1918 Death CEPID at CEPID at 4th Height of Peak Height of Peak City between P1 and Rate school closure Intervention 1 2 P2 Baltimore 601.87 54.31 54.31 215.71 13.60 14.00 Boston 623.13 96.25 125.60 162.23 27.23 13.00 Cincinnatti 430.63 2.09 4.64 68.33 48.63 7.00 Cleveland 428.10 15.08 12.36 87.63 28.15 7.00 Indianapolis 264.75 16.88 16.88 40.63 30.33 6.00 Kansas City 531.23 25.68 5.55 61.23 76.19 6.00 New Orleans 573.27 24.73 29.85 177.27 46.42 12.00 Pittsburgh 647.60 158.43 10.34 132.63 20.90 14.00 St. Louis 346.50 6.23 7.58 31.29 57.46 6.00 Hatchett RJ et al. Proc Natl Acad Sci U S A. 2007 May 1;104(18):7582-7.

Immunology & Vaccines

CoV immunoprotective vs immunopathogenic immune response • Antibody enhancement of infection • Feline enteric CoV (FECV) causes mild or asymptomatic infection • Macrophage tropic variant is feline intestinal peritonitis virus (FIPV) • Antibody to FECV does not protect against FIPV • Enhanced disease seen in animals passively or actively immunized against FIPV but not in those naturally infected Perlman, Nat Rev Immun 2005 • ADE of infection has not been demonstrated in vivo with SARS- CoV vaccines

Antibody enhanced disease with SARS-CoV vaccines • Recombinant vaccinia virus (VV) expressed the SARS-CoV S protein or VV expressing all the structural proteins (N, M, E, and S) of SARS-CoV • Mice immunized with the VV-NMES vaccine developed as severe pneumonia post-SARS-CoV challenge as placebo recipients even though titers of SARS- CoV were reduced to the same extent as the VV-S vaccine • Pathology was not due to vaccine titers • Evaluated VV expressing individual structural proteins • VV-NS vaccinated mice developed anti-N antibodies (non-neutralizing) and anti-S (neutralizing)

Immunopathology of VV expressing N • SARS-CoV vaccine expressing the N protein (VV-N) induced pathology in the lungs of mice following challenge • Immune response induced by the vaccine was a Th2 bias (IL-4, IL-5, and IL- 10) and high expression of IL-6

Inactivated SARS-CoV vaccines • Wild-type SARS-CoV inactivated with formalin and UV, doubly inactivated (DI) & a beta propiolactone-inactivated vaccine (BPV) • These were tested in mice prior to clinical trial use • Compared with a DNA spike protein vaccine • T ested alone and adjuvanted with alum (achieved higher Ab titers) • Evaluated immunogenicity and protective efficacy of the vaccine in young and senescent mice • Challenged with both homologous and heterologous CoV challenge • The vaccine provided protection to young mice but did not provide protection against challenge in old

Eosinophilic infiltration of lungs of mice following DIV SARS-CoV vaccine & challenge • DIV vaccine adjuvanted with alum did not provide protection against homologous and heterologous challenge in aged mice • Both DIV and DIV plus alum vaccines caused enhanced immune pathology in the lungs compared to placebo recipients • Immunopathology occurred in the absence of virus in the lungs • BPV & S DNA vaccines less pathogenic • Cytokine profiles demonstrated Th-2 skewed Tseng, PLoS ONE, 2012 response

DIV vaccination predisposes to enhanced lung pathology Bolles et al J of Virol 2011

What did we learn? • Inactivated SARS-CoV vaccine using formalin and UV irradiation (double- inactivation) as well as BPV protected against SARS pneumonitis but caused immunopathology in the lungs post-challenge in younger mice • Immunized year-old mice (to represent older population) • Assessed homologous and heterologous challenge in mice • Vaccine induced antibodies against S protein and N protein. Antibody titers with Alum adjuvant compared to PBS or VAP adjuvant • Vaccine induced incomplete completion: DIV alone did not significantly reduce titers in the lungs, DIV+ alum reduced titers but to lesser extent in elderly mice • The alum-adjuvanted DIV induced a strong skew in the N- and S-specific antibodies toward IgG1, a subtype associated with Th2 immune responses • Immune pathology was demonstrated following vaccination with the SARS N protein

SARS-CoV-2 immunoprotective vs immunopathogenic immune response • Antibody dependent enhancement of disease was observed with SARS-CoV vaccines • Key to protection against SARS-CoV is the development of neutralizing antibody • SARS-CoV neutralizing antibodies are sufficient to provide complete immunity against lethal SARS challenges in multiple animal models • Appears to be true for SARS-CoV-2 • High enough neutralizing antibody was able to abrogate immunopathology • Vaccines must demonstrate they do not skew to Th2 response in pre-clinical and clinical studies

Protective immune response • SARS-CoV neutralizing antibodies are sufficient to provide complete immunity against lethal SARS challenges in multiple animal models • Appears to be true for SARS-CoV-2 • The N protein is highly immunogenic but does not induce protection and appear to affect the longevity of protective antibodies. • The immune response to the N protein induces immunopathology when it is given along • Induction of enough neutralizing antibodies can protect against SARS-CoV vaccine induced immunopathology • How to induce these antibodies?

Protective immune response • Coronaviruses posses trimeric Spike proteins required for host receptor recognition, binding, and viral entry into cells • The S1 subunit binds host receptors (RBD); the S2 subunit is responsible for membrane fusion • The pre-fusion S protein exists in a meta-stable state: the receptor-binding site on the S1 RBD is occluded when the RBD is in the “in” conformation Pallesen, PNAS, 2017