Norovirus Vaccine Development

Chapter 3.6

Norovirus Vaccine Development

S. Ramani*

M.K. Estes*,**

R.L. Atmar*,**
*    Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, United States
**    Department of Medicine, Baylor College of Medicine, Houston, TX, United States


Noroviruses (NoVs) are a leading cause of sporadic and epidemic gastroenteritis across all age groups worldwide. The increasing recognition of the burden of disease caused by these viruses and their public health impact underscore the need for well tolerated and effective vaccines. In the absence of a completely permissive cell culture system, there is limited possibility of developing live-attenuated or killed NoV vaccines. Despite these challenges, many advances have been made in vaccine development in recent years. A number of vaccine candidates have been evaluated including the production of virus-like particles (VLPs) that are morphologically and antigenically identical to particles of the infectious virus. NoV VLPs appear to be attractive vaccine candidates, and the advances in the area of these vaccines are highly promising. This chapter summarizes data on immune correlates of protection against NoVs, preclinical and clinical studies with NoV candidate vaccines, and discusses the challenges remaining in the field of NoV vaccine development.




virus-like particles


correlates of protection

1. Background

Human noroviruses (NoV) are a leading cause of sporadic and epidemic gastroenteritis across all age groups and are associated with nearly one-fifth of all cases of acute gastroenteritis worldwide (Ahmed et al., 2014). A systematic review of global data showed that NoVs were detected in approximately 24% of acute gastroenteritis cases in the community, 20% of cases in outpatient settings and 17% among inpatients. In the United States, NoV infections result in 19–21 million total illnesses annually, leading to 1.7–1.9 million outpatient visits, 400,000 emergency department visits, 56,000–71,000 hospitalizations and 570–800 deaths (Hall et al., 2013). The economic burden of NoV disease is also high with NoV hospitalizations costing an estimated $500 million annually in the US while foodborne NoV infections result in $2 billion in healthcare and loss of productivity costs (Bartsch et al., 2012). While NoV infections occur in individuals of all age groups, severe outcomes are seen in the elderly and in immunocompromised populations (Bok and Green, 2012Trivedi et al., 2013). NoVs are also important pediatric pathogens, accounting for nearly 12% of diarrheal hospitalizations in children under 5 years of age (Ramani et al., 2014). In countries where rotavirus vaccines are effective, NoVs are rapidly replacing rotavirus as the most common cause of viral gastroenteritis in this age group (Koo et al., 2013Payne et al., 2013). The high clinical and economic impact of NoV disease warrants the need for safe and effective vaccines. While there are currently no licensed NoV vaccines, many candidate vaccines are under development or are in clinical trials.

NoVs are classified into six genogroups (GI–GVI) of which genogroups I, II and IV are known to infect humans (Ramani et al., 2014). The prototype virus Norwalk virus (NV) belongs to genogroup I (GI) while most cases of NoV infections described worldwide are caused by genogroup II (GII) NoVs. In particular, genotype GII.4 is the predominant genotype detected worldwide. The epidemiology of human NoVs is complex and new variants of the GII.4 genotype are known to emerge every 2–3 years, replacing the previously dominant variant. (see Chapter 3.5.) Histo-blood group antigens (HBGAs) are cell attachment factors for many human NoVs (Hutson et al., 2003Lindesmith et al., 2003Huang et al., 2005), and immune pressure-driven antigenic variation in epitopes surrounding the HBGA binding domain of the capsid protein VP1 may contribute to the evolution and emergence of new variants, especially among GII.4 viruses (Lindesmith et al., 2012). This chapter briefly summarizes data on immune responses to NoVs, details the developments and progress in the field of NoV vaccines and highlights the challenges remaining.

2. Immune correlates

A correlate of protection (CoP) can be defined as an immune marker that statistically correlates with protection from infection or illness, be it induced by natural infection or in response to vaccination. Specifically in the case of vaccines, the CoP marker correlates with vaccine efficacy or protection from disease after vaccination. (Plotkin and Gilbert, 2012). The identification of such a marker (or markers) is often based on studies of immune responses to natural infection with the pathogen. Seroprevalence studies in many populations indicate that most adults have high levels of antibodies to NoVs (Greenberg et al., 1979O’Ryan et al., 1998Menon et al., 2013). However, the absence of a fully permissive cell culture system or a small animal models for human NoVs has limited the study of immunity to NoVs. In particular, this poses a problem for performing virus neutralization assays to assess protective immunity.

Much of our understanding of immune responses to natural infection therefore comes from human volunteer challenge studies (Parrino et al., 1977Ryder et al., 1985Johnson et al., 1990Atmar et al., 2014). In one study using NV as the challenge virus, serum IgA levels peaked at day 14 post infection while serum IgG peaked at day 28 (Kavanagh et al., 2011). IgM antibodies were also present in most infected adults. While serological responses to infection were observed in many studies, the data on correlation between protection from disease and levels of antibodies as measured by enzyme linked immunosorbent assays (ELISA) remained inconsistent. The first CoP against NoV disease was identified when it was demonstrated that functional antibodies in serum that block the binding of VLPs to HBGAs reduces the risk of gastroenteritis following challenge with NV (Reeck et al., 2010). This finding was further validated by similar results obtained when the blocking activity was measured using a hemagglutination inhibition assay (Czako et al., 2012). Interestingly, HBGA-blocking antibody responses following NV infection were found to include heterotypic responses (Lindesmith et al., 2010Czako et al., 2015). Although the peak titers of heterotypic antibodies and fold increases in blocking antibody levels were modest in comparison to the response seen with the homologous challenge GI.1 virus, blocking activity was seen against other GI viruses as well as GII.4 variants (Fig. 3.6.1A–C). A particularly remarkable finding was the detection of HBGA-blocking antibodies to GII.4 variants that were not circulating at the time of challenge or sample collection (Fig. 3.6.1B,C). These findings support the possibility of development of broadly cross-protective NoV vaccines using a limited number of NoV strains as immunogens. It is important to note that while data from early volunteer challenge studies suggest that natural infection may not confer long-term protection, a recent mathematical model estimated that immunity following natural NoV infection lasts 4–9 years (Simmons et al., 2013).


Figure 3.6.1 Heterotypic HBGA blocking antibody responses after norovirus infection and NoV VLP vaccination.
Panels A–C show blocking antibody responses following infection with GI.1 virus while panels D–F show blocking antibody responses following vaccination with GI.1.and GII.4c VLPs. Y-axis in panels A, B, D, E represents 50% percent blocking titers (BT50 for infection, EC50 for vaccination as defined in the original studies describing these results) and is defined as the serum titer at which 50% of the VLP-carbohydrate interaction is blocked when compared to the positive control. The geometric mean titers (GMT) of blocking antibodies to GI VLPs following infection and vaccination are seen in Panels A, D respectively. Panels B, E show geometric mean titers (GMT) of blocking antibodies to GII VLPs following infection and vaccination. Shaded cells in panels C and F represent individuals who showed a >fourfold change in blocking antibody response post infection and vaccination, respectively. The response to each NoV genotype or variant is represented by a different color.

Apart from serum HBGA blocking antibodies, mucosal and cellular immunity also appears to play an important role in protection from NoV disease. In a NV volunteer challenge study, NV-specific IgA levels in saliva and stool peaked on day 14 after challenge in the infected participants (Ramani et al., 2015). Antibody-secreting cell (ASC) responses peaked on day 7 and were biased toward IgA. Memory B-cell responses peaked on day 14 and were biased toward IgG. In addition, NV-specific memory B cells but not ASCs persisted 180 days after infection. The study of mucosal and cellular immune responses resulted in the identification of two new potential correlates of protection against NV gastroenteritis. Prechallenge levels of NV-specific salivary IgA and NV-specific IgG memory B cells correlated with protection against NV-gastroenteritis (Ramani et al., 2015). NV-specific salivary IgA levels before challenge correlated with reduced severity of gastroenteritis. In addition, NV-specific fecal IgA levels before challenge were associated with a reduction in peak viral load, whereas fecal IgA measured on day 7 after infection correlated with a shorter duration of virus shedding. A rapid salivary IgA response was previously demonstrated to be associated with protection from infection following challenge with NV in a genetically-susceptible population (Lindesmith et al., 2003). A summary of immune correlates of protection is given in Table 3.6.1.

Table 3.6.1

Immune Correlates of Protection

Correlate Outcome References


Serum histo-blood group antigen (HBGA)-blocking antibody Illness Reeck et al. (2010), Atmar et al. (2011), Atmar et al. (2015)
Infection Atmar et al. (2011), Atmar et al. (2015)
Serum hemagglutination inhibition (HAI) antibody Illness Czako et al. (2012)
Salivary IgA antibody Illness Ramani et al. (2015)
Memory B cells Illness Ramani et al. (2015)
Fecal IgA antibody Peak virus shedding Ramani et al. (2015)


Rapid salivary IgA response Infection Lindesmith et al. (2003)
Day 7 fecal IgA response Duration of virus shedding Ramani et al. (2015)

The efficacy of a vaccine can be measured using clinical end-points or by measuring a CoP that acts as a surrogate marker predicting clinical outcome. Often, the measurement of clinical end-points requires more expensive and effort-intensive study designs. The measurement of a CoP can thus facilitate studies on vaccine efficacy and contribute greatly to vaccine development. The identification of many immune markers or effector molecules that correlate with protection from gastroenteritis in the challenge studies, however, raises the important question on whether there are multiple mechanisms that contribute to protection from NV gastroenteritis. It also raises questions on whether the effector molecules identified are directly responsible for mediating protection or are a reflection of changes in levels of other effector molecules that covary and actually result in protection (mechanistic and nonmechanistic correlates of protection, respectively). These are critical questions in the context of measuring immune response to vaccines and add complexity to study designs for NoV vaccine trials.

3. Preclinical studies with norovirus vaccine candidates

In the absence of efficient cell culture systems to grow human NoVs, the possibility of developing live-attenuated or killed NoV vaccines is limited. However, a number of vaccine candidate for NoVs have been evaluated (Table 3.6.2). The expression of NoV capsid proteins in vitro results in self-assembly of virus-like particles (VLPs) that are morphologically and antigenically identical to particles of the infectious virus (Jiang et al., 1992Green et al., 1993). The production of VLPs was first demonstrated when the NV capsid was produced by expressing the second and third open reading frames of the viral genome in insect cells infected with a recombinant baculovirus (Jiang et al., 1992). VLPs contain 180 copies of the VP1 capsid protein, and their particulate nature may enhance immune activation and uptake by antigen presenting cells in the Peyer’s patches of the gastrointestinal tract. NoV VLPs have been proposed as candidate vaccines since their first description. Preclinical studies evaluated the immunogenicity of VLPs in mice, rabbits, gnotobiotic pigs and chimpanzees using various routes of administration (Table 3.6.3). The effect of different adjuvants on immune response was also tested in several studies.

Table 3.6.2

Norovirus Vaccine Candidates

Antigen Expression system References
Virus-like particles Baculovirus Jiang et al. (1992)
Pichia (yeast) Xia et al. (2007)
Venezuelan equine encephalitis virus replicon Harrington et al. (2002)
Plants (tobacco, potato, tomato) Mason et al. (1996), Zhang et al. (2006)
Recombinant adenovirus Guo et al. (2008)
P particles E. coli Tan and Jiang (2005)

Table 3.6.3

Select Preclinical Studies of NoV Vaccine Candidates

Immunogen Animal Route Adjuvant Findings References
Baculovirus-expressed GI.1/Norwalk VLPs Mice Oral gavage +/– cholera toxin Oral administration of unadjuvanted vaccine induced systemic and mucosal immune responses, and use of adjuvant augmented responses Ball et al. (1998)
Baculovirus-expressed GI.1/Norwalk VLPs Mice Intranasal (IN) versus oral gavage +/− E. coli mutant (R192G) labile toxin (LT) Intranasal administration of unadjuvanted vaccine induced systemic and mucosal immune responses, and use of adjuvant augmented responses at lower dosages than following oral gavage Guerrero et al. (2001)
Baculovirus-expressed GI.1/Norwalk VLPs Mice Intranasal versus oral gavage +/− mutant (E29H) cholera toxin Adjuvant enhanced cellular and serological immune responses, and responses were higher following IN administration compared to the oral route Periwal et al. (2003)
Baculovirus-expressed GII.4/Dijon VLPs Mice Intranasal versus oral gavage +/– E. coli wild type (wt) or mutant (R192G) labile toxin Adjuvant enhanced cellular and serological immune responses, and responses were higher following IN administration compared to the oral route. Responses were similar when wt LT or mutant LT were used as adjuvant Nicollier-Jamot et al. (2004)
Baculovirus-expressed GII.4/HS66 VLPs Gnotobiotic pigs Oral and intranasal E. coli mutant (R192G) labile toxin or ISCOM matrix Both adjuvanted vaccines induced serological and cellular immune responses and were associated with decreased viral shedding and diarrhea after virus challenge compared to control animals Souza et al. (2007)
Baculovirus-expressed GI.1/Norwalk versus GII.4/MD145 VLPs Chimpanzees Intramuscular (IM) Aluminum hydroxide Seroresponses occurred after vaccination; only immunization with the homologous antigen protected against infection following intravenous challenge with Norwalk virus Bok et al. (2011)
GI.1/Norwalk VLPs—tobacco plant extracts and potato expressing VLPs Mice Oral gavage +/– cholera toxin Plant-expressed VLPs were immunogenic Mason et al. (1996)
GII.4/VA387 VLPs—Pichia pastoris-expressed raw extract Mice Oral gavage or intramuscular Ribi adjuvant with IM injection Yeast-expressed VLPs immunogenic after IM delivery and when orally-delivered, induced serum and fecal antibody responses, including production of serum HBGA-blocking antibody Xia et al. (2007)
Venezuelan equine encephalitis (VEE) replicons and VEE replicon-expressed GI.1/Norwalk VLPs Mice Footpad inoculation or oral gavage None Serum antibody responses were induced by both routes of immunization, but the replicon induced higher antibody levels than obtained following oral VLP administration Harrington et al. (2002)
VEE replicons expressing GI.1/Norwalk, GII.1/Hawaii, GII.2/Snow Mountain, GII.4/Lordsdale VLPs Mice Footpad inoculation None Monovalent preparations induced only homotypic HBGA-blocking antibody responses, while a trivalent (GI.1, GII.1, GII.2) preparation induced a heterotypic response to a fourth genotype (GII.4), although to a lesser degree than when the GII.4 strain was included in a vaccination regimen (as monovalent or quadrivalent) LoBue et al. (2006)
GII.4/VA387 P particles expressed in E. coli and yeast Mice Intranasal None P particle vaccine had immunogenicity similar to that achieved using VLPs as the immunogen, including induction of strain-specific HBGA-blocking antibody Tan et al. (2008)
E. coli-expressed GII.4/VA387 P particles and chimeric P particles with rotavirus VP8 Mice Intranasal, subcutaneous Freund’s adjuvant (subcutaneous only) The chimera enhanced responses to VP8 compared to free VP8 delivered IN; it induced immune responses that provided protection against rotavirus challenge in a mouse model; and it induced homotypic norovirus HBGA-blocking antibodies Tan et al. (2011)
GII.4/VA387 baculovirus-expressed VLPs and E. coli-expressed P particles and P dimers Mice Intranasal None VLPs and P particles induced higher levels of antibody and CD4 T cellular immune responses compared to the P dimers Fang et al. (2013)
Baculovirus-expressed GII.4/1999 VLPs; E. coli-expressed GII.4/1999 P particles Mice Intramuscular, intradermal None VLPs induced higher serum antibody levels, heterotypic ELISA antibody responses, more balanced Th1/Th2 antibody response, and IFN-gamma-expressing cellular responses compared to P particles Tamminen et al. (2012)
Baculovirus-expressed GI.3, GII.4/1999, rotavirus rVP6 Mice Intramuscular None Trivalent vaccine induced homotypic and heterotypic serum antibody responses, mucosal antibody responses and T cell responses Tamminen et al. (2013)
E. coli-expressed GII.4/VA387 P dimers or fusion proteins with hepatitis E virus P domain dimers Mice Intranasal None Immunization with the fusion protein induced hepatitis E virus neutralizing antibodies and homotypic norovirus HBGA-blocking antibodies Wang et al. (2014)

Early preclinical studies evaluated the immunogenicity of VLPs in mice. Dose-response and kinetics of serum and intestinal immune responses were evaluated in inbred and outbred mice that were administered NV VLPs orally (Ball et al., 1998). The VLPs were found to be immunogenic when administered in the presence or absence of cholera toxin (CT) as a mucosal adjuvant. The use of CT was associated with the induction of higher levels of serum IgG. Subsequent studies showed that the VLPs were highly immunogenic when administered intranasally, both in the presence and absence of heat-labile toxin of Escherichia coli (LT) as a mucosal adjuvant (Guerrero et al., 2001). In these studies, the intranasal route of delivery was found to be more effective than oral immunization, inducing responses to lower doses of VLPs. Intranasal immunization was also found to induce a stronger immune response compared to oral administration when a modified CT was used as adjuvant (Periwal et al., 2003). The use of CT as an adjuvant resulted in a stronger Th2 type response. Higher numbers of antigen-specific IL-4-producing cells as well as antigen-specific IgA-secreting cells were observed in the Peyer’s patches. Similar results were demonstrated with GII VLPs administered orally or by the intranasal route, with LT or a nontoxic mutant LT as mucosal adjuvant. Intranasal immunization resulted in high serum and fecal IgA responses that were enhanced in the presence of adjuvant (Nicollier-Jamot et al., 2004). A mixed Th1/Th2-like response was observed in cervical lymph nodes and Peyer’s patch cultures with either adjuvant. A dry powder formulation of NV VLPs along with 3-O-desacyl-4′-monophosphoryl lipid A (MPL) as adjuvant and chitosan as a muco adherent induced NV-specific antibody responses in serum and cellular immunity including NV-specific IgA memory B cells in the mesenteric lymph nodes and Peyer’s patches in rabbits (Richardson et al., 2013). In preclinical studies with a bivalent VLP formulation containing NV and GII.4 VLPs in rabbits, higher homologous and heterologous antibody responses were seen following immunization of animals by the intramuscular route when compared to the intranasal route (Parra et al., 2012). In another study, gnotobiotic pigs were vaccinated with human GII.4 VLPs with immune-stimulating complexes or mutant LT as adjuvant (Souza et al., 2007). Both formulations showed high rates of seroconversion and fecal IgA responses as well as protection from live virus infection 28 days after vaccination. VLPs administered with LT induced Th1/Th2 serum cytokines and cytokine-secreting cells, while animals immunized with VLPs and immune-stimulating complexes showed Th2-biased responses. In a chimpanzee model of NV infection, the presence of NV-specific serum antibodies correlated with protection against re-infection at 4, 10, and 24 months following primary infection (Bok et al., 2011). In addition, chimpanzees vaccinated intramuscularly with GI VLPs were protected from NV infection when challenged 2 and 18 months after vaccination.

Apart from baculovirus-expression systems, VLPs produced in a number of other expression systems, such as transgenic plants (tobacco and potatoes), yeast, bacterial expression systems, and alphavirus replicon systems, have also been evaluated in preclinical studies. Recombinant NV (rNV) VLPs expressed in transgenic plants were immunogenic when delivered orally in mice (Mason et al., 1996). Serum IgG antibody was induced in response to the tobacco leaf extracts and potato tubers while NV-specific secretory IgA responses was seen with the plant expressed rNV. Oral administration of raw material from Pichia pastoris yeast lysates that contained GII.4 VLPs resulted in systemic and mucosal immune responses in mice without the use of adjuvants (Xia et al., 2007). In this study, both serum and fecal antibodies blocked the binding of homologous NoV VLPs to HBGA antigens. Venezuelan equine encephalitis (VEE) virus and other alphaviruses have been used as vectors to express heterologous proteins. In this approach, mice subcutaneously inoculated with VEE replicon particles expressing the NV capsid protein developed systemic and mucosal immune responses to the homologous NV VLPs as well as heterotypic antibody responses to another genotype of GI virus (Harrington et al., 2002). The administration of multivalent VEE replicon particles encoding various NoV VLPs induced heterotypic blocking antibody responses, including to a genotype not included in the cocktail (LoBue et al., 2006). With the exception of the Hawaii virus, the monovalent vaccines induced the highest titers of serum IgG response.

A number of other approaches including NoV P-particles, P-dimers, polyvalent norovirus P domain–glutathione-S-transferase (GST) complexes and combination vaccines produced in bacteria have also been evaluated as candidate vaccines (Table 3.6.3). P-particles are 24-mer particles produced in Escherichia coli that comprises the P domain of the NoV capsid. Intranasal immunization of mice with the P particles without an adjuvant or subcutaneous immunization with Freund’s adjuvant resulted in the stimulation of humoral immune response to NoV VLPs (Tan et al., 2008Tan et al., 2011). In addition, P-particles were shown to elicit cellular immunity after intranasal immunization in mice (Fang et al., 2013). Immune responses generated after immunization with VLPs and P-particles were compared in one study (Tamminen et al., 2012). Higher antibody responses were achieved after immunization with a single dose of VLPs whereas a booster dose was required for P-particle immunization. In addition, high avidity antibodies were raised only on immunization with VLPs. VLPs also resulted in a balanced Th1/Th2 type response whereas P-particles induced a Th2-biased response.

Combination vaccines targeting NoV and other viral pathogens are also being developed. In one study, a trivalent combination vaccine was developed consisting of VP1 from a GI NoV and a GII.4 NoV strain along with a tubular form of VP6, the most abundant rotavirus (RV) protein (Tamminen et al., 2013). Each component was produced by a recombinant baculovirus expression system and combined in vitro. High levels of NoV- and RV-specific serum and intestinal IgG antibodies were detected following intramuscular immunization in mice. Serum antibodies blocked binding of homologous and heterologous VLPs to HBGA antigens. A polyvalent complex platform was used to develop a bivalent vaccine against NoV and Hepatitis E virus (HEV) (Wang et al., 2014). Dimeric P domains of NoV and HEV were fused together, linked with dimeric GST and expressed in E. coli. The fusion protein assembled into polyvalent complexes and was found to be immunogenic in mice.

4. Clinical studies

Following preclinical studies that demonstrated the immunogenicity of VLPs, clinical studies were initiated to assess the safety, immunogenicity and efficacy of VLP vaccines in humans (Table 3.6.4). The earliest phase I clinical studies evaluated the safety and immunogenicity of oral immunization with increasing doses of rNV VLPs in healthy adults. In one study, two doses of 100  or 250 μg of the rNV VLP vaccine were administered without adjuvant and a dose-dependent increase in serum IgG responses to rNV VLPs was observed (Ball et al., 1999). All vaccinees who received 250ug of rNV VLPs had a > fourfold increase in serum IgG titers, although most responses were seen after the first dose of vaccine. The vaccine was well tolerated, and no serious adverse events were reported. In another study, healthy adult volunteers received increasing doses of rNV VLP vaccines ranging from 250 to 2000 μg and humoral, mucosal and cellular immune responses were assessed (Tacket et al., 2003). The vaccine was well tolerated, and no volunteer experienced fever, diarrhea or vomiting in the 3 days following vaccination. Three vaccinees reported mild cramps while one person each in the vaccine and placebo arms experienced nausea. Headache and malaise were reported more commonly in the placebo arm of the study. Serum antibody responses were observed in 90% of vaccinees who received two doses of 250 μg of VLPs administered three weeks apart, and there was no further increase in response in the higher dosage groups. All vaccinees developed significant rises in IgA ASCs. Mucosal IgA responses were seen in less than 50% of vaccinees while transient lymphoproliferative and interferon gamma (IFNγ) responses were observed in the two lower dosage groups. Immune responses were also measured in persons who consumed transgenic potatoes expressing the NV capsid protein (Tacket et al., 2000). Although IgG and IgA antibody responses were modest, 95% of vaccinees had a significant increase in virus-specific IgA-ASCs.

Table 3.6.4

Summary of Immunogenicity From Clinical Studies of Norovirus Vaccine Candidates

Vaccine (Manufacturer) Route Dosage (Adjuvant) Schedule Number of Subjects (Age range) Peak Serum IgG GMFR Reported (95% CI) Peak Serum IgA GMFR Reported (95% CI) Serum HAI or HBGA-blocking antibody GMFR Reported (95% CI) References
GI.1/Norwalk (Baylor College of Medicine) Oral 100 mcg (none) 2 doses 3 wks apart 5 (18–46 yrs) 5.3 (1.3–22.3) 3.0 (1.4–6.5) ND Ball et al. (1999)
250 mcg (none) 2 doses 3 wks apart 15 (18–46 yrs) 8.8 (5.4–14.2) 4.4 (2.1–9.2) ND
GI.1/Norwalk (Baylor College of Medicine) Oral 250 mcg (none) 2 doses 3 wks apart 10 (18–40 yrs) ∼13a (NR) NR ND Tacket et al. (2003)
500 mcg (none) 2 doses 3 wks apart 10 (18–40 yrs) ∼13a (NR) NR ND
2000 mcg (none) 2 doses 3 wks apart 10 (18–40 yrs) ∼18a (NR) NR ND
GI.1/Norwalk in potato (Boyce Thompson Institute for Plant Research) Oral 150 g potato containing 215–751 mcg VLP 2 doses 3 wks apart 10 (adult) 8a (not calculable) ND ND Tacket et al. (2000)
150 g potato containing 215–751 mcg VLP 3 doses on days 0, 7, and 21 10 (adult) 13.3a (NR) ND ND
GI.1/Norwalk (Ligocyte/Takeda) Intranasal 5 mcg (chitosan, MPL) 2 doses 3 wks apart 5 (18–49 yrs) 0.9 (NR) 1.2 (NR) ND El-Kamary et al. (2010)
15 mcg (chitosan, MPL) 2 doses 3 wks apart 5 (18–49 yrs) 1.9 (NR) 2.5 (NR) ND
50 mcg (chitosan, MPL) 2 doses 3 wks apart 9 (18–49 yrs) 4.7 (NR) 4.5 (NR) ND
50 mcg (chitosan, MPL) 2 doses 3 wks apart 18 (18–49 yrs) 4.6 (2.5–8.6) 7.6 (4.2–13.8) 4.0 (2.0–7.9)—HAI
100 mcg (chitosan, MPL) 2 doses 3 wks apart 19 (18–49 yrs) 4.8 (3.2–7.1) 9.1 (4.7–17.6) 9.1 (4.0–20.7)—HAI
GI.1/Norwalk (Ligocyte/Takeda) Intranasal 100 mcg (chitosan, MPL) 2 doses 3 wks apart 37 (18–50 yrs) 4.5 (3.1–6.5) 7.5 (4.6–12.2) 3.6 (2.8–4.7) HBGA-blocking Atmar et al. (2011)
GI.1/Norwalk and GII.4/consensus (Ligocyte/Takeda) Intramuscular 5 mcg each (MPL, aluminum hydroxide) 2 doses 4 wks apart 10 (18–49 yrs) NR NR NR Treanor et al. (2014)
15 mcg each (MPL, aluminum hydroxide) 2 doses 4 wks apart 10 (18–49 yrs) NR NR NR
150 mcg each (MPL, aluminum hydroxide) 2 doses 4 wks apart 9 (18–49 yrs) NR NR NR
50 mcg each (MPL, aluminum hydroxide) 2 doses 4 wks apart 18 (18–49 yrs)

GI.1: ∼29 (NR)

GII.4: ∼11 (NR)

GI.1: ∼39 (NR)

GII.4: ∼14 (NR)

GI.1: 16 (NR)

GII.4: 10 (NR) HBGA-blocking

50 mcg each (MPL, aluminum hydroxide) 2 doses 4 wks apart 9 (50–64 yrs)

GI.1: ∼57 (NR)

GII.4: ∼13 (NR)

GI.1: ∼45 (NR)

GII.4: ∼10 (NR)

GI.1: 16 (NR)

GII.4: 11 (NR) HBGA-blocking

50 mcg each (MPL, aluminum hydroxide) 2 doses 4 wks apart 10 (65–85 yrs)

GI.1: (∼13 (NR)

GII.4: ∼6 (NR)

GI.1: ∼42 (NR)

GII.4: ∼5 (NR)

GI.1: 16 (NR)

GII.4: 6 (NR) HBGA-blocking

GI.1/Norwalk and GII.4/consensus (Ligocyte/Takeda) Intramuscular 50 mcg each (MPL, aluminum hydroxide) 2 doses 4 wks apart 49 (18–50 yrs)

GI.1: 27.8 (19.2, 40.2)

GII.4: 8.8 (6.5, 11.9)

GI.1: 17.5 (11.9, 25.8)

GII.4: 9.3 (6.7, 12.7)

GI.1: 31.6 (24.6, 40.5)

GII.4: 7.8 (5.9, 10.2)


Bernstein et al. (2015), Atmar et al. (2015)

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