Anbodies, Vaccines and Passive Immunizaon

Prof Penny Moore

National Institute for Communicable Diseases, a division of the National Health Laboratory Service of South Africa, and the University of the Witwatersrand, Johannesburg, South Africa AVAC, 2015

HIV continues to HIV prevalence in young pregnant women spread at high rates in rural Vulindlela, in some areas! South Africa (2009-2012)

Age Group HIV Prevalence (Years) (N=1029) ≤16 8.4 17-18 18.6 19-20 25.4 21-22 32.8 23-24 44.8

Slide provided by Slim and Quarraisha Abdool Karim, CAPRISA What are the prospects for an HIV vaccine? Why do we need a vaccine In sub-Saharan Africa, of 11 million people eligible for anretroviral therapy, 6.2 million are receiving drugs

Vaccines are very safe, do not rely on adherence or behavior modificaon and generally provide life-long protecon Before Aer vaccines vaccines Vaccines work really well!

Vaccines are among the most successful medical intervenons (eradicated or controlled smallpox, polio, measles…) HIV Vaccine Efficacy Trials To Date

No

NOTE: Phambili (HVTN 503) began to explore a regime similar to STEP in South Africa (not included). The Thai trial (RV144)

31% protecon from infecon through anbodies HVTN 097 (and HVTN100) ALVAC/AIDSVAX B/E in South Africa Phase Ib safety trial in 100 volunteers

Protocol Team HVTN Leadership Laboratory Leadership Glenda Gray Larry Corey Julie McElrath Surita Roux Julie McElrath Georgia Tomaras Nicole Grunenberg Peter Gilbert Erica Andersen-Nissen Edith Swan Glenda Gray David Montefiori Ying Huang Sco Hammer Lynn Morris Ryan Jensen Susan Buchbinder John Hural NIAID/DAIDS Jim Kublin SCHARP Patricia D’Souza SAAVI Ying Huang Phil Renzullo Michelle Mulder Niya Gu Mike Pensiero Sanofi Briany Sanchez USMHRP Carlos DiazGranados Peter Gilbert Jerome Kim Sanjay Phogat Nelson Michael GSID Robb O’Connel Carter Lee Faruk Sinangil

Reason for Opmism!

Vaccinaon can alter risk of acquiring HIV infecon

In the absence of a (good) vaccine…. what can we learn from people infected with HIV, to help us make a vaccine? All infected people make neutralizing anbodies, but not all anbodies are created equal….

Strain-specific anbodies Broadly Neutralizing anbodies

Useful for vaccines? Rare infected people make good anbodies Strain-specific anbodies Broadly Neutralizing anbodies

Gray et al, 2011 Where do these anbodies bind – can we idenfy viral vulnerabilies?

Targets of broad neutralizing anbodies

V2/glycan >12 mAbs

V3/glycan >25 mAbs

CD4bs >25 mAbs MPER >5 mAbs

Modified from Burton et al., Science 2012 What do broadly neutralizing anbodies look like? Fishing for broad neutralizing anbodies Fishing for broad neutralizing anbodies Isolaon of broad monoclonal anbodies

Look backwards to the unmutated common ancestor Fishing for broad neutralizing anbodies Some anbodies are INCREDIBLY broad!

§ We can use these antibodies to understand how they develop and try yo mimic this in vaccines

§ But also more directly in passive immunization studies! Most broad anbodies are “freaks of nature”

Long CDRH3s

Ancestor anbody (how it was born) Highly mutated away from their ancestor Which pathway is easier for HIV vaccine design?

highly mutated Long CDRH3s away from their ancestor

§ Requires a B cell with long § No requirement for long arms arms - these B cells are very rare

§ Once stimulated, these can § May need high levels of develop within months, not mutation that takes years – years hard to achieve through vaccination Acve versus Passive/Vector-based Immunoprophylaxis (VIP)

Vaccinaon Passive “vaccinaon” VIP

Smulang Producon of an anbody anbodies by response Infusion vector with protecve anbodie s

Highly potent anbodies are being tested as “drugs” to prevent HIV Synagis, an anbody used in the clinic

Synagis is used to prevent a serious lung disease caused by respiratory syncyal virus (RSV) .

It is used in infants at high-risk because of prematurity or congenital heart disease.

Anbody is dosed once a month for the duraon of the RSV season.

Tesng passive immunizaon: Does it prevent HIV infecon?

Basic research Preclinical testing Clinical trials

Laboratory Animal studies Human research Discovery Proof-of-concept Safety Efficacy

1- 2 years 1- 2 years 3-5 years Conclusions • Prospects for a vaccine are beer than ever, but this will sll take me

• Passive immunizaon trials in humans will likely provide another HIV prevenon tool and may also be useful for treang people already infected.

• Passive immunizaon will also provide us with informaon we need to drive vaccine design such as which anbody, how much, where?