An$bodies,  Vaccines  and  Passive  

Immuniza$on  

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

Age Group (Years)

HIV Prevalence (N=1029)

≤16 8.4 17-18 18.6 19-20 25.4 21-22 32.8 23-24 44.8

HIV prevalence in young pregnant women

in rural Vulindlela, South Africa (2009-2012)

HIV continues to spread at high rates

in some areas!

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  an@retroviral  therapy,  6.2  million  are  receiving  drugs    

Vaccines  are  very  safe,  do  not  rely  on  adherence  or  behavior  modifica@on  and  generally  provide  life-­‐long  protec@on  

Vaccines  work  really  well!  

Vaccines  are  among  the  most  successful  medical  

interven@ons    (eradicated  or  controlled  

smallpox,  polio,  measles…)  

Before  vaccines  

ALer  vaccines  

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%  protec$on  from  infec$on  

through  an$bodies    

HVTN  097  (and  HVTN100)  ALVAC/AIDSVAX  B/E  in  South  Africa  

Phase  Ib  safety  trial  in  100  volunteers  

Protocol  Team  Glenda  Gray  Surita  Roux  

Nicole  Grunenberg  Edith  Swan  Ying  Huang  Ryan  Jensen  NIAID/DAIDS  

Patricia  D’Souza  Phil  Renzullo  Mike  Pensiero  

USMHRP  Jerome  Kim  

Nelson  Michael  Robb  O’Connel  

HVTN  Leadership  Larry  Corey  

Julie  McElrath  Peter  Gilbert  Glenda  Gray  Sco]  Hammer  

Susan  Buchbinder  Jim  Kublin  SAAVI  

Michelle  Mulder  Sanofi  

Carlos  DiazGranados  Sanjay  Phogat  

GSID  Carter  Lee  

Faruk  Sinangil        

Laboratory  Leadership  Julie  McElrath  

Georgia  Tomaras  Erica  Andersen-­‐Nissen  

David  Montefiori  Lynn  Morris  John  Hural  SCHARP  

Ying  Huang  Niya  Gu  

Bri]any  Sanchez  Peter  Gilbert  

Reason  for  Op$mism!    

Vaccina$on  can  alter  risk  of  acquiring  HIV  infec$on      

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  an$bodies,  but  not  all  an$bodies  are  created  equal….  

Useful  for  vaccines?  

Strain-­‐specific  an$bodies   Broadly  Neutralizing  an$bodies  

Rare  infected  people  make  good  an$bodies  Strain-­‐specific  an$bodies   Broadly  Neutralizing  an$bodies  

Gray  et  al,  2011  

Where  do  these  an$bodies  bind  –  can  we  iden$fy  viral  vulnerabili$es?  

V2/glycan >12 mAbs

V3/glycan >25 mAbs

MPER >5 mAbs

Modified from Burton et al., Science 2012

Targets  of  broad  neutralizing  an$bodies  

CD4bs

>25 mAbs

What  do  broadly  neutralizing  an$bodies  look  like?  

Fishing  for  broad  neutralizing  an$bodies  

Fishing  for  broad  neutralizing  an$bodies  

Look  backwards  to  the  unmutated  common  ancestor  

Isola@on  of  broad  monoclonal  an@bodies  

Fishing  for  broad  neutralizing  an$bodies  

Some  an$bodies  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!

Long  CDRH3s  

Highly  mutated  away  from  their  ancestor  

Most  broad  an$bodies  are  “freaks  of  nature”  

Ancestor  an@body  (how  it  was  born)  

Long  CDRH3s   highly  mutated  away  from  their  

ancestor  

Which  pathway  is  easier  for  HIV  vaccine  design?  

§  Requires a B cell with long arms - these B cells are very rare

§  Once stimulated, these can develop within months, not years

§  No requirement for long arms

§  May need high levels of mutation that takes years – hard to achieve through vaccination

Ac$ve  versus  Passive/Vector-­‐based    Immunoprophylaxis  (VIP)  

Vaccina@on  

S@mula@ng      an  an@body  response  

Passive  “vaccina@on”  

Infusion  with  protec@ve  an@bodies  

Produc@on  of  an@bodies  by  vector  

VIP  

Highly  potent  an$bodies  are  being  tested  as  “drugs”  to    

prevent  HIV  

Synagis  is  used  to  prevent  a  serious  lung  disease  caused  by  respiratory  syncy@al  virus  (RSV)  .      It  is  used  in  infants  at  high-­‐risk  because  of  prematurity  or  congenital  heart  disease.      An@body  is  dosed  once  a  month  for  the  dura@on  of  the  RSV  season.    

Synagis,  an  an$body  used  in  the  clinic    

Basic research

Preclinical testing

Clinical trials

Discovery Human research Animal studies Laboratory

Proof-of-concept

1-­‐  2  years   3-­‐5  years  

Tes$ng  passive  immuniza$on:    Does  it  prevent  HIV  infec$on?  

Safety Efficacy

1-­‐  2  years  

Conclusions  •  Prospects  for  a  vaccine  are  be]er  than  ever,  but  this  will  s@ll  take  @me  

•  Passive  immuniza@on  trials  in  humans  will  likely  provide  another  HIV  preven@on  tool  and  may  also  be  useful  for  trea@ng  people  already  infected.    

•  Passive  immuniza@on  will  also  provide  us  with  informa@on  we  need  to  drive  vaccine  design  such  as  which  an@body,  how  much,  where?