Vaccine strategies to overcome maternal antibody mediated inhibition of measles vaccine

PII: SO264-410X(98)00112-1

Vaccine, Vol. 16, No. 14/15, pp. 1479-1481, 1998 0 1998 Elsevier Science Ltd. All rights reserved Printed in Great Britain 0264-410X198 $19+0.00

ELSEVIER

Vaccine st:rategies to overcome maternal iantibody mediated inhibition of measles vaccine Albert Osterhaus*$,, Geert van Amerongent

and Robert van Binnendijk?

A vaccine that is effktive in the presence of maternally derived virus neutralizing antibodies and can be administered successfully at an early age, would be favoured over the presently used live attenuated measles vaccines. With the advent of new molecular and immunological techniques, several options for the development of new generation vaccines, fulfilling these criteria, have arisen. We have recently evaluated the ejjkacy of recombinant vaccinia virus- and iscom-based candidate vaccines, presenting the F and H proteins of measles virus, in macaques with passively transferred virus neutralizing macaque antibodies. The data indicate that the further exploration of the potential of iscom based measles vaccines should be encouraged. 0 1998 Elsevier Science Ltd. All rights reserved. Keywords:

measles; maternal

antibodies; vaccines

Vaccination against measles with live attenuated measles vaccines was introduced in the sixties and has been quite successful in controlling measles in industrialized countries. In developing countries, however, measles is still a major cause of morbidity and mortality in infants, with more than one million children dying from measles worldwide annually’. Although this may at least in part be attributed to low vaccination coverage in many developing countries, another major problem is the interference by maternally derived measles virus (MV) specific antibodies present at the time of vaccination. Therefore, a vaccine that would be effective in the presence of MV neutralizing antibodies and could be administered successfully at an early age when the infants immune system is not yet fully mature, would strongly be favoured over the presently used live attenuated measles vaccines2. A first attempt in thi:s direction was the use of hightitred live attenuated measles vaccines, which had been shown to result in increased sero-conversion rates in young infants and could partly overcome the problem of pre-existing MV neutralizing antibodies. However, the use of these vaccines proved to be associated with an increased mortality in children during the first years following vaccination in certain developing countries3. With the advent of new molecular and immunological techniques, several options for the use of new generation vaccines have arisen. *Institute of Virology, Erslsmus University Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. tNational Institute of Public Health .and the Environment, P.O. Box 1, 3720 BA Bilthoven, The Netherlands. SAuthor to whom all Tel.: addressed. shoiJd be correspondence +31-10-4088066; Fax: +31-10-4365145

NOVEL VACCINE GENERATIONS AND NEW VACCINATION STRATEGIES Among the approaches presently considered to develop a second generation measles vaccines, are the use of new attenuated measles viruses and recombinant viruses expressing the relevant measles proteins, the use of nucleic acid vaccination techniques as well as the use of viral subunits takin advantage of new 5 adjuvants and adjuvant systems . Furthermore, new routes of application, instead of the presently practised intramuscular and subcutaneous should routes, seriously be considered, with the present and new generation vaccines. An important issue in considering the introduction of such new generations of measles vaccines for infants is an observation made in the sixties, when tween-ether and formaldehyde-inactivated virus preparations were introduced as new measles vaccines4. These vaccines induced only limited protection and cases of so-called atypical measles (AMS) were observed when the vaccinees were subsequently exposed to wild type MV. Although the underlying immune mediated mechanisms leading to AMS are not fully understood at present, both the induction of qualitatively and quantitatively aberrant MV specific antibody and T cell responses have been implicated. Studies are ongoing in animal models addressing the mechanisms involved, and it will be clear that before a new generation can be introduced, sufficient vaccine measles safeguards should be obtained from these models, indicating that similar aberrant immune responses are not induced. The use of live attenuated measles vaccines, which are presently all based on the Edmonston B strain of MV, leads to a sero-conversion rate of more than 95%

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Vaccine strategies and maternal antibody inhibition: A. Osterhaus et al.

and a very high protective efficacy if properly administered in the absence of MV neutralizing antibodies. Compared with natural infection, side reactions are very mild. Another major advantage of using live attenuated vaccines is that the nature of the induced immunity closely resembles that of the immunity after recovery from natural MV infection, albeit that the attenuation may have led to a uantitatively and qualitatively lower immune response %. This may be the reason why wild type MV many continue to circulate on mucosal membranes of the respiratory tract of vaccinees with waning immunity, as has for example been observed during recent outbreaks of measles in Europe. This may have major implications for ongoing elimination and eradication strategies. So far the molecular basis of MV attenuation has not been identified. However, the recent production of infectious molecular clones of MV may allow the identification of the molecular basis of attenuation and thus the engineering of newly attenuated measles vaccines by means of site directed mutagenesis. To evaluate the interference of MV specific antibodies with the efficacy of live attenuated MV vaccines, we have vaccinated cynomolgous macaques in the presence of different levels of passively acquired MV specific macaque serum antibodies’.‘. We showed that as little as 0.1 IU of MV neutralizing antibody per ml of serum abrogated the induction of specific IgM, IgG and MV neutralizing antibodies by live attenuated measles vaccine (Table 1). However, challenge of these animals about one year later with wild type MV, showed that these animals were largely protected, with the level of protection depending on the level of antibodies present at the time of vaccination. The MV specific T cell response that was induced by vaccination

in the presence of the passively transferred antibodies probably mediated this protection (Table 2)2. The availability of a macaque-MV infection model in which the negative effect of pre-existing MV specific antibodies on the efficacy of the current live attenuated vaccination procedure has been evaluated2, now provides an adequate tool to evaluate the efficacy of novel generations of vaccines and their application routes, in the presence of pre-existing MV specific antibodies. We have also studied the potential of live recombinant viruses, expressing the MV genes encoding viral proteins believed to be involved in the induction of protective immunity against MV infection. To this end we have evaluated the potential of recombinant pox viruses expressing the F and H proteins of MV, for their capacity to induce protective immunity against wild type MV challenge, when administered in the presence or absence of passively transferred 0.16 IU MV neutralizing antibody per ml of serum’. Vaccination of macaques twice intradermally with 10h.’p.f.u. of recombinant vaccinia virus-FH (rVV-FH) in the absence of specific antibodies resulted in levels of MV neutralizing antibodies of up to 1.5 IU per ml serum. Vaccination with the same rVV-FH in the presence of the 0.16 IU MV neutralizing antibodies did not result in a MV specific antibody response. Revaccination with the same vaccine when the antibody titres had dropped to 0.08 IU per ml serum resulted in a light increase of MV neutralizing antibody levels which were, however, significantly lower than those observed in the animals vaccinated with rVV-FH in the absence of specific antibodies (Table I)‘. In all the macaques vaccinated with rVV-FH in the presence or absence of the MV neutralizing antibodies, specific proliferative T cell

Table 1 Serum antibody response of macaques vaccinated with live attenuated presence or absence of passively transferred macaque serum antibodies

Vaccine LA-MV

rW-FH MV-iscom

(LA-MV), rW-FH

and MV iscom in the

MV neutralizing serum antibody titre (IU ml-‘) at time of vaccination

LA-MV isolation from PBMC” at 1 week

IgM at 2-3 weeks (GD,,, nm)

IgG at 4 weeks

VN (IU ml-‘) at 4 weeks

<0.08 0.08 0.16 10.08 0.16 CO.08 0.16

+ _ _ _ _ _

> 0.5 < 0.3 co.3 <0.3 <0.3 >0.5 >0.5

> 2000 < 250 < 250 >lOOO <250 >10000 > 10000

>2.5 <0.2 <0.2 > 1 .o <0.2 >30 >30

“PBMC = peripheral

blood mononuclear

cells

Table 2 Protection of macaques (Table 1) from intratracheal presence or absence of passively transferred antibodies Vaccine

None LA-MV

rW-FH MV-iscom

“PBMC = peripheral

1480

measles vaccine

wild type MV (Wl-MV)

challenge

MV neutralizing serum antibody titre (IU ml - 1) at time of vaccination

PBMC”

LLC”


> 300 _ 5 _ _ 5 5 5

> 300 _ 5 100 5 50 10 5

blood mononuclear

WT-MV isolation (inf. cells/106 cells) during first week, from:

cells; LLC = lung lavage cells.

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about one year after vaccination

in the

> fivefold MV neutralizing serum antibody titre rise after challenge + _ + + + + + +

Vaccine strategies and maternal antibody inhibition:

responses were identified2 (not shown). As was the case for the macaques vaccinated with live attenuated measles vaccine in the presence of MV neutralizing antibodies, all the macaques vaccinated with rVV-FH, were partially protected from wild type MV challenge about one year later. Protection was most pronounced in the animals vaccinated with rVV-FH in the absence of the MV neutralizing antibodies (Table 2)“. This indicated that the presence of these antibodies at the time of vaccination did interfere with the induction of specific antibodies, but to a lesser extent with the induction of specific T cell responses on basis of which still a relative protection from wild type MV challenge could be demonstrated. Using the same syste:m we have also evaluated the potential of a candidate subunit vaccine, based on immune stimulating complexes (iscoms) presenting the F and H proteins of measles virus. Iscoms have been shown to be highly effective in inducing high levels of biologically active antibodies, cell mediated immunity and protection in several virus systems’. Especially the induction of MHC class I restricted CD8’ CTL responses as well as mucosal antibody responses by iscoms, prompted us to evaluate this adjuvant system for the vaccination of macaques with a MV subunit preparation, in the presence and absence of MV neutralizing antibodies. Intramuscular vaccination of macaques twice with 10 pg of the F and H proteins in iscoms led to high levels of specific IgM and IgG serum antibodies, as well as, to MV neutralizing serum antibody levels of up to 80 IU per ml. The presence of 0.16 IU per ml of MV neutralizing serum antibodies at the time of vaccination did not interfere with the induction of these MV specific serum antibodies upon vaccination with the lrscom preparation (Table I)‘. Similarly, no clear differences were found in MV specific proliferative responses in macaques vaccinated in the presence or absence of MV neutralizing antibodies, and the proliferative responses were similar to those observed in the macaques vaccinated with rVV-FH2 (not shown). Challenge of the iscom vaccinated macaques about one year later with wild type MV, showed a partial but significant protection of all the thus vaccinated animals,

A. Osterhaus et al.

largely irrespective of the presence or absence of specific antibodies at the time of vaccination (Table 2)‘. Collectively these data show that macaques vaccinated with live attenuated measles vaccine, rVV-FH and MV iscoms, irrespective of their serologic response on vaccination in the presence or absence of MV specific antibodies are largely protected from challenge with wild type MV. It should be stressed, however, that the studies presented were limited by the use of low levels of passively transferred antibodies and by a challenge carried out about one year after vaccination only. The issue of a possible immature immune system was not addressed in these studies. Data obtained with iscoms in several other systems have shown that this presentation system allows the induction of protective immune responses in neonates of several animal species. Therefore, the further exploration of the potential of MV iscoms, to induce protective immunity in the presence of higher levels of specific antibodies of maternal origin in baby macaques should be a logical next step. Also the evaluation of administration of new candidate vaccines via mucosal routes should be encouraged. REFERENCES Katz, S.L. and Gellin, B.G. Measles vaccine: do we need new vaccines or new programs. Science 1994, 265,1391-l 392. Van Binnendijk, R.S., Poelen, M.C.M., Van Amerongen, G., De Vries, P. and Osterhaus, A.D.M.E. Protective immunity in macaques vaccinated with live attenuated, recombinant, and subunit measles vaccines in the presence of passively acquired antibodies. J. Infect. Dis. 1997, 175, 524-532. Garenne, M., Leroy, O., Beau, J.P. and Sene, I. Child mortality after high-titre measles vaccines: prospective study in Senegal. Lancet 1991,336,903-907. Osterhaus, A.D.M.E., De Vries, P. and Van Binnendijk, R.S. Measles vaccines: novel generations and new strategies. J. fnfect Dis. 1994, 170, S42-S55. Van Binnendijk, R.S., Van der Heijden, R.W.J., Van Amerongen, G., UytdeHaag, F.G.C.M. and Osterhaus, A.D.M.E. Viral replication and development of specific immunity in macaques after infection with different measles virus strains. J. fnfecf. Dis. 1994, 170, 443-446. Rimmelzwaan, G.F. and Osterhaus, A.D.M.E. fscoms: materials, preparation, antigen delivery and immune response. In: Antigen Delivery Systems (Eds Gander, B., Merkle, H.P. and Corradin, G.). Harwood, Switzerland, 1997, pp. 123-139.

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