Advertisement
  • Loading metrics

Harnessing early life immunity to develop a pediatric HIV vaccine that can protect through adolescence

Harnessing early life immunity to develop a pediatric HIV vaccine that can protect through adolescence

  • Ria Goswami, 
  • Stella J. Berendam, 
  • Shuk Hang Li, 
  • Ashley N. Nelson, 
  • Kristina De Paris, 
  • Koen K. A. Van Rompay, 
  • Sallie R. Permar, 
  • Genevieve G. Fouda
PLOS
x

Need for an earlylife HIV vaccine

The successful implementation of antiretroviral therapy (ART) in women living with HIV (WLWH), either for their own health or for prevention of mother-to-child transmission (MTCT), has reduced MTCT risk of HIV to <5% [1]. Yet, in 2018, worldwide, approximately 160,000 infants were infected with HIV [2]. The currently available ART-based measures to prevent MTCT in WLWH are limited by implementation challenges, such as suboptimal ART coverage of pregnant and breastfeeding women [3], poor adherence to ART [4,5] resulting in incomplete viral suppression and increased risk of drug resistance, and late presentation for prenatal care [6]. In addition, ART-based prophylactic strategies do not address the scenario of acute maternal infections that occur late during pregnancy or during the breastfeeding period [7]. While breastfeeding is critical to reduce infant mortality in resource-limited settings by providing nutrition and protection against common childhood diseases, it also contributes to >50% of new infant HIV infections. Therefore, to prevent MTCT and achieve an HIV-free generation, novel immune-based intervention strategies beyond ART need to be explored. While these immune-based strategies could be administered either to pregnant women or to infants in the form of active immunization or passive immunization, this review primarily focuses on active immunization of neonates with an HIV vaccine that can protect during early life, from breast milk transmission, and during adolescence, from sexual transmission.

In addition to the risk of HIV infections that occur early in life via breastfeeding, sexual transmission during adolescence and adulthood also represents a significant and ongoing mode of infection [8]. A pediatric HIV vaccine administered at birth and boosted during infancy may protect infants during the period of repetitive HIV exposure via breastfeeding. Additionally, sequential boosting through childhood and preadolescence may allow for the maturation of their immune responses and the development of broadly protective immunity prior to sexual debut, including HIV-specific broadly neutralizing antibodies (bNabs), which can neutralize a diverse variety of HIV strains by targeting conserved viral epitopes. Passive immunization with bNabs has been shown to be associated with modest and transient suppression of viremia in humans [9] and in animal models [10,11]. Consequently, elicitation of bNabs is a major goal for an efficacious HIV vaccine. Since bNab development requires years of affinity maturation and somatic hypermutation (SHM), the period between breastfeeding and sexual debut represents a unique “window of opportunity” to boost anti-HIV antibody responses at a time when the risk of HIV infection is low. Thus, a vaccine strategy initiated at birth and pursued through adolescence may protect an individual from infancy through adulthood (Fig 1).

thumbnail
Fig 1. Early life vaccination to achieve protection from bimodal HIV acquisition.

An HIV vaccine administered at birth with successive boosting during infancy will induce anti-HIV neutralizing and non-neutralizing antibody responses and HIV-specific cellular immunity that will reduce the risk of HIV infection via breastfeeding. Moreover, immunization started at birth and boosted during infancy, childhood and preadolescence will provide those neutralizing antibodies sufficient time to mature, undergo extensive affinity maturation, and SHM and enhance their breadth and strength prior to sexual debut. These developed bNabs will confer protection against sexual transmission of HIV during adulthood. bNabs, broadly neutralizing antibodies; SHM, somatic hypermutation.

https://doi.org/10.1371/journal.ppat.1008983.g001

Several recent studies have indicated that the early life immune system may present some advantages for elicitation of HIV-specific antibody responses. The purpose of this review is to summarize these studies and highlight the unique ability of the early life developing immune system to mount robust and durable immune responses against HIV, compared to adults. Additionally, the potential of harnessing neonatal immune ontogeny to develop an effective earlylife HIV vaccine is emphasized.

Infants can develop robust and durable responses to HIV vaccination

Owing to maturational differences in the early life and adult immune systems, the ability of infants to generate vaccine-specific immune responses has traditionally been considered as impaired [reviewed in [12]]. Additionally, there are concerns around vaccine safety in infants, possible interference of passively acquired maternal antibodies with the development of protective immune responses [13], and interference of novel vaccines with commonly administered childhood vaccines [14]. These factors are further complicated by the inability of the child to provide approval of participation in the trial, challenges of obtaining parental consent for the child to participate due to perceived risks of the trial [15], and the constraint of limited blood volumes obtained from infants for immunogenicity evaluations. As a consequence, only a restricted number of infant vaccine trials have been conducted, to date. Nevertheless, increasing evidence indicates that infants can mount robust and durable immune responses following vaccination, demonstrating that earlylife immune system is not unresponsive. In fact, it is increasingly recognized that qualitative and quantitative differences between infant and adult immune system are critical for the adaptation of early-life immune system to the ex utero environment [reviewed in [16]].

Neonatal nonhuman primate (NHP) studies have provided encouraging results regarding the ability of infants to mount durable immune responses against HIV or simian immunodeficiency virus (SIV) vaccines [1719]. In fact, the concept of vaccination at birth to protect through infancy and adolescence was highlighted by a study demonstrating that immunization of neonatal rhesus macaques (RM) with poxvirus-based SIV vaccines early after birth provided partial protection against multiple low-dose SIV challenges not only during infancy but also during adolescence [20]. Other studies have also demonstrated that HIV vaccination can induce robust antibody responses in infant RMs, although the protective roles of these antibodies were not investigated in that cohort [21].

To date, only a few pediatric HIV vaccine trials have been completed (Table 1). While none of these vaccine trials was designed to evaluate vaccine efficacy, these trials have consistently confirmed a good safety profile in infants. All these trials have indicated that vaccinated infants could develop robust and durable antigen-specific humoral and cell-mediated immune responses, despite the use of different antigens, adjuvants, and viral vectors. To determine whether infants were capable of eliciting potentially protective responses, antibody responses from infant HIV vaccinees (Pediatric AIDS Clinical Trials Group [PACTG] 230 and PACTG 326 trials) (Table 1) were compared to those of the vaccine recipients from the RV144 trial, the only adult HIV vaccine trial that resulted in moderate efficacy [22]. Immune correlate analysis of RV144 indicated an association between a higher magnitude of immunoglobulin G (IgG) responses against the envelope variable loops 1 and 2 (V1V2) with reduced risk of HIV acquisition, whereas envelope-specific immunoglobulin A (IgA) responses were associated with increased risk of HIV acquisition [23]. Infants from both trials mounted robust V1V2-specific IgG responses, yet vaccine-elicited Env-specific IgA responses were rarely detected. Interestingly, the frequency of V1V2 IgG response of infants immunized with MF-59-adjuvanted rgp120 vaccine (Chiron, United States of America) (PACTG 230 trial) was also higher than that of RV144 vaccinees, and high magnitude antibody responses were still detected more than 6 months after immunization [24]. Since RV144 vaccinees received a different vaccine regimen than PACTG vaccinees, the ability of infants to mount V1V2 IgG responses at a higher magnitude than adults was further confirmed by comparing the antibody responses between infants and adults immunized with similar vaccine regimens [25]. Additionally, the presence of maternal antibodies did not interfere with the infants’ ability to mount antibody responses [24,26], and immunization with HIV vaccine during infancy did not inhibit the ability of other childhood vaccines to induce protective antibody levels [27,28].

Development of protective broadly neutralizing antibody responses and non-neutralizing responses in young children

Although the induction of cross-clade bNab is 1 of the major goals of any HIV vaccination strategy [36,37], so far, no HIV vaccine regimen has successfully elicited such responses. Therefore, understanding the immune mechanisms behind generation of such bNab responses remains the number 1 priority in the HIV vaccination research. During natural infection, bNabs develop only in 10% to 30% of the HIV-infected adults after several years of infection and are associated with extensive SHM and affinity maturation [38,39]. In contrast, HIV-infected children can develop broad neutralization earlier than adults [4043] and exhibit increase in neutralization breadth and potency over time [41,44]. Moreover, compared to adults, where plasma neutralization breadth is driven by antibodies of limited specificities, neutralization breadth in children is often achieved via polyclonal epitope specificity [40,45]. To date, the 2 bNabs isolated from children demonstrated absence of extensive SHM [43,46]. The mutational changes that are critical for bNab functionality were revealed to be distinct in pediatric population compared to adults [47]. Mutations important for the functional activity of 1 isolated pediatric bNab were primarily found in the heavy chain complementarity-determining region 2 (HCDR2) and light chain complementarity-determining region 1(LCDR1), in contrast to adult bNabs, where major determinant of breadth reside in the heavy chain complementarity-determining region 3 (HCDR3) [47]. For the other isolated pediatric bNab, unlike adult bNabs, indels in the heavy chain framework 3 region (HFR3) seemed to be critical for neutralization breadth [43]. Additionally, neutralization breadth in children was found to be associated with several immune parameters such as T follicular helper (Tfh) cells, circulating T follicular regulatory (Tfr) cells [48], and T helper cell 2 (Th2) cytokine interleukin 5 (IL-5) levels in plasma [49]. These findings suggest that neutralization breadth in children is driven by distinct mechanisms than in adults. Therefore, to augment our understanding of the advantage of early immune landscape on the development of neutralization breadth and to provide possible leverage in the quest of protective pediatric HIV vaccination regimens, further isolation, and characterization of pediatric bNabs will be crucial. Understanding the immune mechanisms, evolutionary pathways, and mutational changes that are critical for bNab development and activity in early life will be crucial for designing effective HIV vaccines.

While elicitation of bNabs remains a priority of HIV vaccine development, a combination of neutralizing and non-neutralizing effector responses might be crucial for an efficacious vaccine. A recent study has indicated that polyfunctional antibody responses are predictive of bNab development [50], suggesting that the pathways for induction of neutralizing and non-neutralizing effector functions are not completely distinct. In the RV144 adult HIV vaccine trial, non-neutralizing IgG antibody-dependent cellular cytotoxicity (ADCC)-associated antibodies were correlated with reduced risk of HIV infection [23]. Additionally, non-neutralizing antibody responses were correlated with protection induced by HIV vaccine candidates in adult RM models [51,52]. In infants, the presence of non-neutralizing antibodies capable of ADCC functions has been associated with better clinical outcomes, during breastfeeding [53]. Therefore, it might be postulated that upon HIV immunization at birth, prior to the development of bNabs, non-neutralizing antibody responses such as ADCC might confer some level of protection against breastmilk transmission (Fig 1). Interestingly, while only a short-lived ADCC response was detectable in infant HIV vaccinees from the PACTG 230 trial [24] (Table 1), durable HIV-specific ADCC responses were obtained in infant RMs immunized with an HIV vaccine [54], suggesting that further studies involving non-neutralizing antibody responses in the context of pediatric HIV vaccination are necessary.

Modulating the early life immune landscape to augment protective anti-HIV immunity

Newborns transition from a relatively sheltered intrauterine environment to an environment with multiple antigenic exposures. To obtain survival benefits during the period of immune maturation, newborns establish a highly tolerogenic environment and exhibit a distinct immune profile than adults [reviewed in [16]]. Therefore, to optimally design a pediatric vaccine regimen tailored to the developing infant’s immune landscape, understanding earlylife immune ontogeny remains crucial.

Use of age-relevant adjuvants

While alum has been the standard adjuvant of choice for commercial pediatric vaccines, HlV pediatric vaccine trials have reported the superiority of MF-59 adjuvant in mounting potent and durable antibody responses when compared to alum. In PACTG 230 trial, the MF-59-adjuvanted vaccine formulation was associated with durable anti-Env IgG responses, which was associated with higher breadth and durability as compared to the alum-adjuvanted counterpart [24]. This indicates that proper selection of adjuvants will be essential to augment infant vaccination responses. The ability of adjuvants to differentially modulate immune responses in different age groups has only recently started to be appreciated [55]. Since infants exhibit an intrinsic bias toward Th2 responses, an effective HIV vaccine might require adjuvants that enhance Th1 responses. Indeed, incorporation of the TLR7/8 agonist adjuvant 3M-052, which can prime antigen presenting cells (APCs) by producing interleukin 12 (IL-12), in alum-adjuvanted pneumococcal vaccines (PCV), facilitated Th1 differentiation and significantly enhanced antibody responses in infant RMs immunized at birth [56]. Similarly, a recent study in infant RMs demonstrated a potential advantage of TLR-based adjuvants, AS01-TLR4 agonist and 3M-052-TLR7/8 agonist, on the induction of robust HIV-specific antibody responses compared to squalene or alum [57], although the protective efficacy of those elicited HIV antibodies was not investigated. Therefore, further exploration of age-specific mechanisms of adjuvant effects will be required to develop potent and durable pediatric HIV vaccines.

Alterations of the infant microbiome to optimize vaccine responses

Emerging evidence suggests that an individual’s microbiome can influence immune responses to vaccination [58]. Therefore, variations in microbial communities due to environmental, socioeconomic, and nutritional conditions partially explain the heterogeneity of an individual’s vaccine response [59]. While the mechanisms through which the microbiome modulate immune responses are likely complex and are not clearly defined, microbiota have been associated with a constant source of natural adjuvants that can shape one’s innate and adaptive immunity [60]. This endogenous adjuvant potential of microbiota was highlighted in a study where germ-free or antibiotic-treated mice had significantly impaired response to an inactivated influenza vaccine [61]. Additionally, an oral probiotic regimen augmented antibody response to multiple vaccines [62,63]. In contrast, the microbiome can also adversely impact vaccine efficacy by skewing antibody response toward non-protective antigens that resemble commensal bacterial antigens [reviewed in [64]]. In the setting of HIV vaccination, the preexisting B cell repertoire that develops against the commensal microbiota may divert the vaccine-elicited immune responses toward the gp41 region of vaccine candidates, as opposed to the more desirable neutralizing epitopes contained within the gp120 subunit [65]. Therefore, altering the existing gut microbiota in early infancy, when the B cell repertoire is predominantly naïve, could be beneficial to direct the immune response, upon vaccination, toward protective immunity. In fact, the first 2 years of life represents the perfect “window of opportunity” to perform microbial modulations, since the microbiome remains highly plastic during the time when maternal stimuli, nutrition, and introduction to solid foods, metabolism, and the environment are major contributors that shape microbial diversity [reviewed in [66]].

Next-generation immunogens for pediatric vaccine trials

Neonates and infants possess unique immunological characteristics that promote the development of protective immunity via immunological and molecular pathways distinct from those of adults. Therefore, a deeper understanding of the infant immune system is needed to develop novel HIV immunization regimens tailored to the infant’s immune landscape. The fact that the most recent adult HIV vaccine trial (HVTN 702), done in South Africa, which tested a canarypox vector-based vaccine (ALVAC-HIV) with HIV subtype C gp120 protein adjuvanted with MF-59, was recently discontinued due to lack of efficacy [67] highlights the need to evaluate promising next-generation immunogens. To mimic the natural development of specific bNab lineages, a sequential immunization approach using HIV envelope sequences from patients who developed bNabs is currently being pursued in preclinical models [68,69]. Since in most cases natural evolution of a B cell lineage is unknown, an alternative approach is to design envelope constructs with specific antigenic features to target the bNab germline [70]. Epitope-based vaccine approaches consisting of envelope constructs that incorporate a portion of the bNab epitope to obtain a focused immune response are also currently being evaluated [reviewed in [71]]. The neonatal B cell compartment primarily consists of naïve and B cells [72] with high germinal center B cell activity, lower frequency of regulatory B cells, and limited diversity of B cell repertoire. Hence, early life may offer a unique opportunity to enhance B cell priming following vaccination, thereby providing potential advantages toward the development of bNabs. Additionally, infants demonstrate distinct B cell tolerance mechanism compared to adults [73,74], which could be a beneficial strategy of engaging and positively selecting B cells expressing specific germline immunoglobulin gene sequences. Other novel immunogen approaches that are currently being evaluated in adults include native-like envelope trimer immunogens [75], fold-on trimers [76], native flexible-linked (NFL) trimers [77], DNA vaccines encoding polyvalent gp120s [78], and mRNA vaccine [79]. While recent studies in adults have demonstrated the existence of bNab precursors [80], their frequency in pediatric population is largely unknown. Therefore, to assess whether pediatric immune system presents advantages for induction of neutralization breadth, novel immunization strategies need to be evaluated in pediatric preclinical models [81].

The pediatric HIV vaccine protocol HVTN 135 is currently in development to assess the safety and immunogenicity of HIV CH505 transmitted-founder (T/F) gp120 adjuvanted with the TLR4 agonist GLA-SE in HIV-exposed infants. This Phase I trial will use the CH505 T/F protein that is currently being tested in an adult HIV vaccine trial, and the results from HVTN135 will determine if this vaccine is safe to be used in infants. Additionally, this trial will indicate whether infants develop a distinct immune response to this vaccine as compared to adults, hence providing valuable information for the design of future pediatric HIV vaccine trials. Ultimately, additional clinical trials will be required to assess if immunization at birth can protect infants from vertical HIV transmission during infancy and against sexual HIV transmission during adolescence.

References

  1. 1. WHO. Mother-to-child transmission of HIV. Available from: https://www.who.int/hiv/topics/mtct/about/en/.
  2. 2. UNAIDS. Global HIV & AIDS statistics—2019 fact sheet. Available from: https://www.unaids.org/en/resources/fact-sheet.
  3. 3. AVERT. PREVENTION OF MOTHER-TO-CHILD TRANSMISSION (PMTCT) OF HIV 2020. Available from: https://www.avert.org/professionals/hiv-programming/prevention/prevention-mother-child.
  4. 4. Ngarina M, Popenoe R, Kilewo C, Biberfeld G, Ekstrom AM. Reasons for poor adherence to antiretroviral therapy postnatally in HIV-1 infected women treated for their own health: experiences from the Mitra Plus study in Tanzania. BMC Public Health. 2013;13:450. Epub 2013 May 8. pmid:23647555; PubMed Central PMCID: PMC3651864.
  5. 5. Millar JR, Bengu N, Fillis R, Sprenger K, Ntlantsana V, Vieira VA, et al. HIGH-FREQUENCY failure of combination antiretroviral therapy in paediatric HIV infection is associated with unmet maternal needs causing maternal NON-ADHERENCE. EClinicalMedicine. 2020;22:100344. Epub 2020 Jun 9. pmid:32510047; PubMed Central PMCID: PMC7264978.
  6. 6. Momplaisir FM, Brady KA, Fekete T, Thompson DR, Diez Roux A, Yehia BR. Time of HIV Diagnosis and Engagement in Prenatal Care Impact Virologic Outcomes of Pregnant Women with HIV. PLoS ONE. 2015;10(7):e0132262. Epub 2015 Jul 2. pmid:26132142; PubMed Central PMCID: PMC4489492.
  7. 7. UNAIDS. Get on the fast-track: The Life-cycle approach to HIV. Available from: http://www.unaids.org/sites/default/files/media_asset/Get-on-the-Fast-Track_en.pdf.
  8. 8. UNICEF. Statistical Tables 2019. Available from: https://data.unicef.org/topic/hivaids/global-regional-trends/.
  9. 9. Caskey M, Klein F, Lorenzi JC, Seaman MS, West AP Jr, Buckley N, et al. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature. 2015;522(7557):487–91. Epub 2015 Apr 10. pmid:25855300; PubMed Central PMCID: PMC4890714.
  10. 10. Shingai M, Nishimura Y, Klein F, Mouquet H, Donau OK, Plishka R, et al. Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia. Nature. 2013;503(7475):277–80. Epub 2013 Nov 1. pmid:24172896; PubMed Central PMCID: PMC4133787.
  11. 11. Klein F, Halper-Stromberg A, Horwitz JA, Gruell H, Scheid JF, Bournazos S, et al. HIV therapy by a combination of broadly neutralizing antibodies in humanized mice. Nature. 2012;492(7427):118–22. Epub 2012 Oct 30. pmid:23103874; PubMed Central PMCID: PMC3809838.
  12. 12. Siegrist CA. The challenges of vaccine responses in early life: selected examples. J Comp Pathol. 2007;137(Suppl 1):S4–9. Epub 2007 Jun 15. pmid:17559867.
  13. 13. Borras E, Urbiztondo L, Costa J, Batalla J, Torner N, Plasencia A, et al. Measles antibodies and response to vaccination in children aged less than 14 months: implications for age of vaccination. Epidemiol Infect. 2012;140(9):1599–606. Epub 2011 Nov 15. pmid:22074684.
  14. 14. Halasa NB, O’Shea A, Shi JR, LaFleur BJ, Edwards KM. Poor immune responses to a birth dose of diphtheria, tetanus, and acellular pertussis vaccine. J Pediatr. 2008;153(3):327–32. Epub 2008 Jun 7. pmid:18534242; PubMed Central PMCID: PMC3773719.
  15. 15. Greenberg RG, Gamel B, Bloom D, Bradley J, Jafri HS, Hinton D, et al. Parents’ perceived obstacles to pediatric clinical trial participation: Findings from the clinical trials transformation initiative. Contemp Clin Trials Commun. 2018;9:33–9. Epub 2018 Apr 27. pmid:29696222; PubMed Central PMCID: PMC5898566.
  16. 16. Martinez DR, Permar SR, Fouda GG. Contrasting Adult and Infant Immune Responses to HIV Infection and Vaccination. Clin Vaccine Immunol. 2016;23(2):84–94. Epub 2015 Dec 15. pmid:26656117; PubMed Central PMCID: PMC4744916.
  17. 17. Rasmussen RA, Hofmann-Lehman R, Montefiori DC, Li PL, Liska V, Vlasak J, et al. DNA prime/protein boost vaccine strategy in neonatal macaques against simian human immunodeficiency virus. J Med Primatol. 2002;31(1):40–60. Epub 2002 Jun 22. pmid:12076047.
  18. 18. Van Rompay KK, Greenier JL, Cole KS, Earl P, Moss B, Steckbeck JD, et al. Immunization of newborn rhesus macaques with simian immunodeficiency virus (SIV) vaccines prolongs survival after oral challenge with virulent SIVmac251. J Virol. 2003;77(1):179–90. Epub 2002 Dec 13. pmid:12477823; PubMed Central PMCID: PMC140621.
  19. 19. Han Q, Bradley T, Williams WB, Cain DW, Montefiori DC, Saunders KO, et al. Neonatal rhesus macaques have distinct immune cell transcriptional profiles following HIV envelope immunization. Cell Rep. 2020;30(5):1553–69.e6. Epub 2020 Feb 6. pmid:32023469; PubMed Central PMCID: PMC7243677.
  20. 20. Van Rompay KK, Abel K, Lawson JR, Singh RP, Schmidt KA, Evans T, et al. Attenuated poxvirus-based simian immunodeficiency virus (SIV) vaccines given in infancy partially protect infant and juvenile macaques against repeated oral challenge with virulent SIV. J Acquir Immune Defic Syndr. 2005;38(2):124–34. Epub 2005 Jan 27. pmid:15671796.
  21. 21. Phillips B, Fouda GG, Eudailey J, Pollara J, Curtis AD II, Kunz E, et al. Impact of Poxvirus Vector Priming, Protein Coadministration, and Vaccine Intervals on HIV gp120 Vaccine-Elicited Antibody Magnitude and Function in Infant Macaques. Clin Vaccine Immunol. 2017;24(10). Epub 2017 Aug 18. pmid:28814388; PubMed Central PMCID: PMC5629672.
  22. 22. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med. 2009;361(23):2209–20. Epub 2009 Oct 22. pmid:19843557.
  23. 23. Haynes BF, Gilbert PB, McElrath MJ, Zolla-Pazner S, Tomaras GD, Alam SM, et al. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N Engl J Med. 2012;366(14):1275–86. Epub 2012 Apr 6. pmid:22475592; PubMed Central PMCID: PMC3371689.
  24. 24. Fouda GG, Cunningham CK, McFarland EJ, Borkowsky W, Muresan P, Pollara J, et al. Infant HIV type 1 gp120 vaccination elicits robust and durable anti-V1V2 immunoglobulin G responses and only rare envelope-specific immunoglobulin A responses. J Infect Dis. 2015;211(4):508–17. Epub 2014 Aug 30. pmid:25170104; PubMed Central PMCID: PMC4318918.
  25. 25. McGuire EP, Fong Y, Toote C, Cunningham CK, McFarland EJ, Borkowsky W, et al. HIV-Exposed Infants Vaccinated with an MF59/Recombinant gp120 Vaccine Have Higher-Magnitude Anti-V1V2 IgG Responses than Adults Immunized with the Same Vaccine. J Virol. 2018;92(1). Epub 2017 Oct 13. pmid:29021402; PubMed Central PMCID: PMC5730786.
  26. 26. McFarland EJ, Johnson DC, Muresan P, Fenton T, Tomaras GD, McNamara J, et al. HIV-1 vaccine induced immune responses in newborns of HIV-1 infected mothers. AIDS. 2006;20(11):1481–9. Epub 2006 Jul 19. pmid:16847402.
  27. 27. Itell HL, McGuire EP, Muresan P, Cunningham CK, McFarland EJ, Borkowsky W, et al. Development and application of a multiplex assay for the simultaneous measurement of antibody responses elicited by common childhood vaccines. Vaccine. 2018;36(37):5600–8. Epub 2018 Aug 9. pmid:30087048; PubMed Central PMCID: PMC6130906.
  28. 28. Afolabi MO, Ndure J, Drammeh A, Darboe F, Mehedi SR, Rowland-Jones SL, et al. A phase I randomized clinical trial of candidate human immunodeficiency virus type 1 vaccine MVA.HIVA administered to Gambian infants. PLoS ONE. 2013;8(10):e78289. Epub 2013 Nov 10. pmid:24205185; PubMed Central PMCID: PMC3813444.
  29. 29. Lambert JS, McNamara J, Katz SL, Fenton T, Kang M, VanCott TC, et al. Safety and immunogenicity of HIV recombinant envelope vaccines in HIV-infected infants and children. National Institutes of Health-sponsored Pediatric AIDS Clinical Trials Group (ACTG-218). J Acquir Immune Defic Syndr Hum Retrovirol. 1998;19(5):451–61. Epub 1998 Dec 22. pmid:9859958.
  30. 30. Borkowsky W, Wara D, Fenton T, McNamara J, Kang M, Mofenson L, et al. Lymphoproliferative responses to recombinant HIV-1 envelope antigens in neonates and infants receiving gp120 vaccines. AIDS Clinical Trial Group 230 Collaborators. J Infect Dis. 2000;181(3):890–6. Epub 2000 Mar 18. pmid:10720509.
  31. 31. Cunningham CK, Wara DW, Kang M, Fenton T, Hawkins E, McNamara J, et al. Safety of 2 recombinant human immunodeficiency virus type 1 (HIV-1) envelope vaccines in neonates born to HIV-1-infected women. Clin Infect Dis. 2001;32(5):801–7. Epub 2001 Mar 7. pmid:11229849.
  32. 32. Johnson DC, McFarland EJ, Muresan P, Fenton T, McNamara J, Read JS, et al. Safety and immunogenicity of an HIV-1 recombinant canarypox vaccine in newborns and infants of HIV-1-infected women. J Infect Dis. 2005;192(12):2129–33. Epub 2005 Nov 17. pmid:16288378.
  33. 33. Kaleebu P, Njai HF, Wang L, Jones N, Ssewanyana I, Richardson P, et al. Immunogenicity of ALVAC-HIV vCP1521 in infants of HIV-1-infected women in Uganda (HPTN 027): the first pediatric HIV vaccine trial in Africa. J Acquir Immune Defic Syndr. 2014;65(3):268–77. Epub 2013 Oct 5. pmid:24091694; PubMed Central PMCID: PMC4171956.
  34. 34. Kintu K, Andrew P, Musoke P, Richardson P, Asiimwe-Kateera B, Nakyanzi T, et al. Feasibility and safety of ALVAC-HIV vCP1521 vaccine in HIV-exposed infants in Uganda: results from the first HIV vaccine trial in infants in Africa. J Acquir Immune Defic Syndr. 2013;63(1):1–8. Epub 2012 Dec 12. pmid:23221981; PubMed Central PMCID: PMC3625520.
  35. 35. Njuguna IN, Ambler G, Reilly M, Ondondo B, Kanyugo M, Lohman-Payne B, et al. PedVacc 002: a phase I/II randomized clinical trial of MVA.HIVA vaccine administered to infants born to human immunodeficiency virus type 1-positive mothers in Nairobi. Vaccine. 2014;32(44):5801–8. Epub 2014 Sep 1. pmid:25173484; PubMed Central PMCID: PMC4414927.
  36. 36. IAVI. Broadly Neutralizing Antibodies. Available from: https://www.iavi.org/our-science/broadly-neutralizing-antibodies.
  37. 37. NIAID. A Theoretical Approach To HIV Vaccine Development. Available from: https://www.niaid.nih.gov/diseases-conditions/theoretical-approach.
  38. 38. Landais E, Huang X, Havenar-Daughton C, Murrell B, Price MA, Wickramasinghe L, et al. Broadly neutralizing antibody responses in a large longitudinal sub-saharan HIV primary infection cohort. PLoS Pathog. 2016;12(1):e1005369. Epub 2016 Jan 15. pmid:26766578; PubMed Central PMCID: PMC4713061.
  39. 39. Mikell I, Sather DN, Kalams SA, Altfeld M, Alter G, Stamatatos L. Characteristics of the earliest cross-neutralizing antibody response to HIV-1. PLoS Pathog. 2011;7(1):e1001251. Epub 2011 Jan 21. pmid:21249232; PubMed Central PMCID: PMC3020924.
  40. 40. Goo L, Chohan V, Nduati R, Overbaugh J. Early development of broadly neutralizing antibodies in HIV-1-infected infants. Nat Med. 2014;20(6):655–8. Epub 2014 May 27. pmid:24859529; PubMed Central PMCID: PMC4060046.
  41. 41. Makhdoomi MA, Khan L, Kumar S, Aggarwal H, Singh R, Lodha R, et al. Evolution of cross-neutralizing antibodies and mapping epitope specificity in plasma of chronic HIV-1-infected antiretroviral therapy-naive children from India. J Gen Virol. 2017;98(7):1879–91. Epub 2017 Jul 12. pmid:28696188.
  42. 42. Muenchhoff M, Adland E, Karimanzira O, Crowther C, Pace M, Csala A, et al. Nonprogressing HIV-infected children share fundamental immunological features of nonpathogenic SIV infection. Sci Transl Med. 2016;8(358):358ra125. Epub 2016 Sep 30. pmid:27683550; PubMed Central PMCID: PMC6087524.
  43. 43. Kumar S, Panda H, Makhdoomi MA, Mishra N, Safdari HA, Chawla H, et al. An HIV-1 Broadly Neutralizing Antibody from a Clade C-Infected Pediatric Elite Neutralizer Potently Neutralizes the Contemporaneous and Autologous Evolving Viruses. J Virol. 2019;93(4). Epub 2018 Nov 16. pmid:30429339; PubMed Central PMCID: PMC6364018.
  44. 44. Mishra N, Makhdoomi MA, Sharma S, Kumar S, Dobhal A, Kumar D, et al. Viral characteristics associated with maintenance of elite neutralizing activity in chronically HIV-1 clade C-infected monozygotic pediatric twins. J Virol. 2019;93(17). Epub 2019 Jun 21. pmid:31217240; PubMed Central PMCID: PMC6694815.
  45. 45. Ditse Z, Muenchhoff M, Adland E, Jooste P, Goulder P, Moore PL, et al. HIV-1 Subtype C-Infected Children with Exceptional Neutralization Breadth Exhibit Polyclonal Responses Targeting Known Epitopes. J Virol. 2018;92(17). Epub 2018 Jun 29. pmid:29950423; PubMed Central PMCID: PMC6096808.
  46. 46. Simonich CA, Williams KL, Verkerke HP, Williams JA, Nduati R, Lee KK, et al. HIV-1 Neutralizing Antibodies with Limited Hypermutation from an Infant. Cell. 2016;166(1):77–87. Epub 2016 Jun 28. pmid:27345369; PubMed Central PMCID: PMC4930401.
  47. 47. Simonich CA, Doepker L, Ralph D, Williams JA, Dhar A, Yaffe Z, et al. Kappa chain maturation helps drive rapid development of an infant HIV-1 broadly neutralizing antibody lineage. Nat Commun. 2019;10(1):2190. Epub 2019 May 18. pmid:31097697; PubMed Central PMCID: PMC6522554.
  48. 48. Roider J, Maehara T, Ngoepe A, Ramsuran D, Muenchhoff M, Adland E, et al. High-Frequency, Functional HIV-Specific T-Follicular Helper and Regulatory Cells Are Present Within Germinal Centers in Children but Not Adults. Front Immunol. 2018;9:1975. Epub 2018 Sep 28. pmid:30258437; PubMed Central PMCID: PMC6143653.
  49. 49. Roider J, Porterfield JZ, Ogongo P, Muenchhoff M, Adland E, Groll A, et al. Plasma IL-5 but Not CXCL13 Correlates With Neutralization Breadth in HIV-Infected Children. Front Immunol. 2019;10:1497. Epub 2019 Jul 25. pmid:31333650; PubMed Central PMCID: PMC6615198.
  50. 50. Richardson SI, Chung AW, Natarajan H, Mabvakure B, Mkhize NN, Garrett N, et al. HIV-specific Fc effector function early in infection predicts the development of broadly neutralizing antibodies. PLoS Pathog. 2018;14(4):e1006987. Epub 2018 Apr 10. pmid:29630668; PubMed Central PMCID: PMC5908199.
  51. 51. Bradley T, Pollara J, Santra S, Vandergrift N, Pittala S, Bailey-Kellogg C, et al. Pentavalent HIV-1 vaccine protects against simian-human immunodeficiency virus challenge. Nat Commun. 2017;8:15711. Epub 2017 Jun 9. pmid:28593989; PubMed Central PMCID: PMC5472724.
  52. 52. Barouch DH, Stephenson KE, Borducchi EN, Smith K, Stanley K, McNally AG, et al. Protective efficacy of a global HIV-1 mosaic vaccine against heterologous SHIV challenges in rhesus monkeys. Cell. 2013;155(3):531–9. Epub 2013 Nov 19. pmid:24243013; PubMed Central PMCID: PMC3846288.
  53. 53. Milligan C, Richardson BA, John-Stewart G, Nduati R, Overbaugh J. Passively acquired antibody-dependent cellular cytotoxicity (ADCC) activity in HIV-infected infants is associated with reduced mortality. Cell Host Microbe. 2015;17(4):500–6. Epub 2015 Apr 10. pmid:25856755; PubMed Central PMCID: PMC4392343.
  54. 54. Curtis AD II, Dennis M, Eudailey J, Walter KL, Cronin K, Alam SM, et al. HIV Env-Specific IgG Antibodies Induced by Vaccination of Neonatal Rhesus Macaques Persist and Can Be Augmented by a Late Booster Immunization in Infancy. mSphere. 2020;5(2). Epub 2020 Mar 28. pmid:32213623; PubMed Central PMCID: PMC7096624
  55. 55. Sanchez-Schmitz G, Stevens CR, Bettencourt IA, Flynn PJ, Schmitz-Abe K, Metser G, et al. Microphysiologic Human Tissue Constructs Reproduce Autologous Age-Specific BCG and HBV Primary Immunization in vitro. Front Immunol. 2018;9:2634. Epub 2018 Dec 14. pmid:30524426; PubMed Central PMCID: PMC6256288.
  56. 56. Dowling DJ, van Haren SD, Scheid A, Bergelson I, Kim D, Mancuso CJ, et al. TLR7/8 adjuvant overcomes newborn hyporesponsiveness to pneumococcal conjugate vaccine at birth. JCI Insight. 2017;2(6):e91020. Epub 2017 Mar 30. pmid:28352660; PubMed Central PMCID: PMC5360187 from VentiRx Pharmaceuticals, 3M Drug Delivery Systems, MedImmune, Crucell (Johnson & Johnson), and Shire.
  57. 57. Phillips B, Van Rompay KKA, Rodriguez-Nieves J, Lorin C, Koutsoukos M, Tomai M, et al. Adjuvant-Dependent Enhancement of HIV Env-Specific Antibody Responses in Infant Rhesus Macaques. J Virol. 2018;92(20). Epub 2018 Aug 10. pmid:30089691; PubMed Central PMCID: PMC6158427.
  58. 58. Hagan T, Cortese M, Rouphael N, Boudreau C, Linde C, Maddur MS, et al. Antibiotics-Driven Gut Microbiome Perturbation Alters Immunity to Vaccines in Humans. Cell. 2019;178(6):1313–28.e13. Epub 2019 Sep 7. pmid:31491384; PubMed Central PMCID: PMC6750738.
  59. 59. Velasquez DE, Parashar U, Jiang B. Decreased performance of live attenuated, oral rotavirus vaccines in low-income settings: causes and contributing factors. Expert Rev Vaccines. 2018;17(2):145–61. Epub 2017 Dec 19. pmid:29252042.
  60. 60. Pabst O, Hornef M. Gut microbiota: a natural adjuvant for vaccination. Immunity. 2014;41(3):349–51. Epub 2014 Sep 23. pmid:25238091.
  61. 61. Oh JZ, Ravindran R, Chassaing B, Carvalho FA, Maddur MS, Bower M, et al. TLR5-mediated sensing of gut microbiota is necessary for antibody responses to seasonal influenza vaccination. Immunity. 2014;41(3):478–92. Epub 2014 Sep 16. pmid:25220212; PubMed Central PMCID: PMC4169736.
  62. 62. de Vrese M, Rautenberg P, Laue C, Koopmans M, Herremans T, Schrezenmeir J. Probiotic bacteria stimulate virus-specific neutralizing antibodies following a booster polio vaccination. Eur J Nutr. 2005;44(7):406–13. Epub 2004 Dec 4. pmid:15578195.
  63. 63. Olivares M, Diaz-Ropero MP, Sierra S, Lara-Villoslada F, Fonolla J, Navas M, et al. Oral intake of Lactobacillus fermentum CECT5716 enhances the effects of influenza vaccination. Nutrition. 2007;23(3):254–60. Epub 2007 Mar 14. pmid:17352961.
  64. 64. Karst SM. The influence of commensal bacteria on infection with enteric viruses. Nat Rev Microbiol. 2016;14(4):197–204. Epub 2016 Feb 9. pmid:26853118; PubMed Central PMCID: PMC5198578.
  65. 65. Williams WB, Liao HX, Moody MA, Kepler TB, Alam SM, Gao F, et al. HIV-1 VACCINES. Diversion of HIV-1 vaccine-induced immunity by gp41-microbiota cross-reactive antibodies. Science. 2015;349(6249):aab1253. Epub 2015 Aug 1. pmid:26229114; PubMed Central PMCID: PMC4562404.
  66. 66. Chong CYL, Bloomfield FH, O’Sullivan JM. Factors Affecting Gastrointestinal Microbiome Development in Neonates. Nutrients. 2018;10(3). Epub 2018 Mar 3. pmid:29495552; PubMed Central PMCID: PMC5872692.
  67. 67. NIAID. Experimental HIV Vaccine Regimen Ineffective in Preventing HIV 2020. Available from: https://www.niaid.nih.gov/news-events/experimental-hiv-vaccine-regimen-ineffective-preventing-hiv.
  68. 68. Saunders KO, Verkoczy LK, Jiang C, Zhang J, Parks R, Chen H, et al. Vaccine Induction of Heterologous Tier 2 HIV-1 Neutralizing Antibodies in Animal Models. Cell Rep. 2017;21(13):3681–90. Epub 2017 Dec 28. pmid:29281818; PubMed Central PMCID: PMC5777169.
  69. 69. Williams WB, Zhang J, Jiang C, Nicely NI, Fera D, Luo K, et al. Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations. Nat Commun. 2017;8(1):1732. Epub 2017 Nov 25. pmid:29170366; PubMed Central PMCID: PMC5701043.
  70. 70. Stamatatos L, Pancera M, McGuire AT. Germline-targeting immunogens. Immunol Rev. 2017;275(1):203–16. Epub 2017 Jan 31. pmid:28133796; PubMed Central PMCID: PMC5741082.
  71. 71. Andrabi R, Bhiman JN, Burton DR. Strategies for a multi-stage neutralizing antibody-based HIV vaccine. Curr Opin Immunol. 2018;53:143–51. Epub 2018 May 19. pmid:29775847; PubMed Central PMCID: PMC6141341.
  72. 72. Duchamp M, Sterlin D, Diabate A, Uring-Lambert B, Guerin-El Khourouj V, Le Mauff B, et al. B-cell subpopulations in children: National reference values. Immun Inflamm Dis. 2014;2(3):131–40. Epub 2014 Dec 17. pmid:25505547; PubMed Central PMCID: PMC4257758.
  73. 73. Jeyakanthan M, Meloncelli PJ, Zou L, Lowary TL, Larsen I, Maier S, et al. ABH-Glycan Microarray Characterizes ABO Subtype Antibodies: Fine Specificity of Immune Tolerance After ABO-Incompatible Transplantation. Am J Transplant. 2016;16(5):1548–58. Epub 2015 Nov 26. pmid:26602221.
  74. 74. Kohler S, Engmann R, Birnbaum J, Fuchs A, Kaczmarek I, Netz H, et al. ABO-compatible retransplantation after ABO-incompatible infant heart transplantation: absence of donor specific isohemagglutinins. Am J Transplant. 2014;14(12):2903–5. Epub 2014 Oct 9. pmid:25293954.
  75. 75. O’Connell RJ, Excler JL, Polonis VR, Ratto-Kim S, Cox J, Jagodzinski LL, et al. Safety and Immunogenicity of a Randomized Phase 1 Prime-Boost Trial With ALVAC-HIV (vCP205) and Oligomeric Glycoprotein 160 From HIV-1 Strains MN and LAI-2 Adjuvanted in Alum or Polyphosphazene. J Infect Dis. 2016;213(12):1946–54. Epub 2016 Feb 26. pmid:26908741; PubMed Central PMCID: PMC4878724.
  76. 76. Kovacs JM, Noeldeke E, Ha HJ, Peng H, Rits-Volloch S, Harrison SC, et al. Stable, uncleaved HIV-1 envelope glycoprotein gp140 forms a tightly folded trimer with a native-like structure. Proc Natl Acad Sci U S A. 2014;111(52):18542–7. Epub 2014 Dec 17. pmid:25512514; PubMed Central PMCID: PMC4284565.
  77. 77. Sharma SK, de Val N, Bale S, Guenaga J, Tran K, Feng Y, et al. Cleavage-independent HIV-1 Env trimers engineered as soluble native spike mimetics for vaccine design. Cell Rep. 2015;11(4):539–50. Epub 2015 Apr 22. pmid:25892233; PubMed Central PMCID: PMC4637274.
  78. 78. Vaine M, Wang S, Crooks ET, Jiang P, Montefiori DC, Binley J, et al. Improved induction of antibodies against key neutralizing epitopes by human immunodeficiency virus type 1 gp120 DNA prime-protein boost vaccination compared to gp120 protein-only vaccination. J Virol. 2008;82(15):7369–78. Epub 2008 May 23. pmid:18495775; PubMed Central PMCID: PMC2493346.
  79. 79. Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines—a new era in vaccinology. Nat Rev Drug Discov. 2018;17(4):261–79. Epub 2018 Jan 13. pmid:29326426; PubMed Central PMCID: PMC5906799.
  80. 80. Jardine JG, Kulp DW, Havenar-Daughton C, Sarkar A, Briney B, Sok D, et al. HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen. Science. 2016;351(6280):1458–63. Epub 2016 Mar 26. pmid:27013733; PubMed Central PMCID: PMC4872700.
  81. 81. Nelson AN, Goswami R, Dennis M, Tu J, Mangan RJ, Saha PT, et al. Simian-Human Immunodeficiency Virus SHIV.CH505-Infected Infant and Adult Rhesus Macaques Exhibit Similar Env-Specific Antibody Kinetics, despite Distinct T-Follicular Helper and Germinal Center B Cell Landscapes. J Virol. 2019;93(15). Epub 2019 May 17. pmid:31092583; PubMed Central PMCID: PMC6639294.